Natural Product Treatment for Metabolic Dysfunction-Associated Steatotic Liver Disease: Targeted Mitochondrial Quality Control

Introduction

Metabolically associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), has emerged as the most common chronic liver disease worldwide, affecting roughly one-third of the adult population and up to two-thirds of individuals with type 2 diabetes or obesity.¹ It is primarily characterized by hepatic steatosis and the presence of at least one cardiometabolic risk factor, including obesity, type 2 diabetes mellitus (T2DM), insulin resistance, hypertension, or dyslipidemia.² The diagnosis requires exclusion of other primary causes of steatosis, such as alcohol-related liver disease, drug-induced liver injury, viral hepatitis, or other chronic liver diseases, monogenic disorders, and other secondary causes of steatotic liver disease, in accordance with current EASL/AASLD consensus definitions.³ In 2023, a multisociety Delphi consensus adopted the MASLD/MASH nomenclature to reflect metabolic roots and enhance clinical clarity, an agenda now integrated into hepatology guidance and coding.⁴ This terminological shift reflects a deeper conceptual reframing: MASLD is no longer just passive hepatic fat accumulation, but rather an active manifestation of systemic metabolic derangement encompassing insulin resistance, dyslipidemia, ectopic lipid deposition, and altered hepatic lipid flux.⁵ At the cellular level, mitochondria are central integrators of nutrient flux, redox homeostasis, and hepatocyte fate. Accumulating evidence indicates that impaired mitochondrial metabolism and defective mitochondrial quality control (MQC), encompassing dynamics, mitophagy, biogenesis, and proteostasis, are early and persistent drivers of MASLD progression.⁶ Hepatic lipid overload and insulin resistance impose sustained metabolic pressure on hepatocyte mitochondria, leading to β-oxidation overload, increased electron transport chain flux, excessive ROS production, and lipid peroxidation.⁷ MQC defects can further amplify these damages, including mitochondrial fusion/fission imbalance and suppressed mitophagy.^8,9 The recent approval of the thyroid hormone receptor-β agonist resmetirom, along with encouraging data for GLP-1 receptor agonists such as semaglutide and newer incretin-based polyagonists, represents a milestone in pharmacotherapy; however, these agents primarily target systemic metabolic pathways and do not directly engage MQC circuitry.^3,10 In parallel, a growing body of preclinical and early clinical studies suggests that natural products, including traditional Chinese medicine–derived compounds and formulas, can remodel mitochondrial homeostasis and attenuate steatosis, inflammation, and cell death in MASLD models, often through multi-target, network-level actions.¹¹

Building on prior reviews that have independently examined mitochondrial dysfunction in NAFLD and the hepatoprotective properties of natural products, this article foregrounds MQC as the overarching mechanistic architecture that integrates these domains. Within this unified framework, we systematically delineate how natural products recalibrate mitochondrial integrity in MASLD through their actions on dynamics, mitophagy, biogenesis, and proteostasis, while simultaneously providing a critical appraisal of their pharmacological mechanisms, potential toxicological liabilities, and the extent to which these agents can be advanced as MQC-targeted therapeutic candidates in translational settings.

Overview of Mitochondrial Quality Control Modules

Mitochondrial quality control is a multilayered defense system that enables cells to preserve the structural and functional integrity of mitochondria, maintaining energy metabolism and cellular homeostasis by repairing damaged components, clearing dysfunctional mitochondria, and replenishing new organelles. At the molecular level, mitochondrial proteostasis is maintained by molecular chaperones and proteases, and the mitochondrial unfolded protein response (UPR^mt) is triggered when protein damage exceeds the repair capacity.¹² Chaperones (eg, HSP60, HSP10) and proteases (eg, LONP1, CLPP) remove or refold damaged proteins; when this capacity is exceeded, UPR^mt is activated.¹³ At the organelle level, selective removal of dysfunctional mitochondria via PINK1–Parkin-mediated mitophagy is a core mechanism; loss of Parkin, a RBR E3 ubiquitin protein ligase (PARKIN), accelerates steatosis and fibrosis in fatty liver models, and restoring mitophagy ameliorates disease progression.^9,14 MQC also governs the selective propagation of functional mtDNA and metabolic rewiring that preserves ATP homeostasis under stress.¹⁵ Significantly, these MQC modules are differentially perturbed in MASLD, making MQC both a mechanistic nexus of disease progression and a promising therapeutic target.

The term “mitochondrial dysfunction” is frequently invoked in MASLD, yet it conflates several mechanistically distinct processes, offering little precision for biomarker development or targeted therapy. Accumulating experimental and clinical evidence indicates that specific arms of MQC (dynamics, mitophagy, and biogenesis) are differentially impaired in MASLD, driving disease progression. In human NASH liver biopsies, the fusion protein mitofusin 2 (MFN2) is markedly reduced, and hepatocyte-specific Mfn2 deletion in mice induces steatosis, inflammation, and even hepatocarcinogenesis, highlighting fusion failure as a discrete pathogenic node rather than generic “dysfunction”.⁸ Likewise, mitophagy loss represents an early and measurable vulnerability: PARKIN-deficient mice develop accelerated steatosis, insulin resistance, and fibrosis, and a TNFα/Miz1 feedback loop that suppresses mitophagy has been shown to propagate NASH.⁹ Mitochondrial biogenesis is also selectively compromised; fatty liver models exhibit inadequate induction of PGC-1α-dependent biogenesis during metabolic stress, while biopsies from NAFLD patients display reduced markers of mitochondrial turnover and impaired fatty acid oxidation.¹⁶ Together, these findings underscore that “mitochondrial dysfunction” is too broad to be mechanistically or therapeutically beneficial. The pathogenesis of MASLD is better understood by identifying which MQC modules fail, and therapeutic strategies—including natural products—should be evaluated for their ability to restore these specific MQC axes.

Liver–Mitochondria Interaction in MASLD

The liver is a solid organ composed of parenchyma and interstitium, supplied by a dual blood supply from the portal vein, rich in nutrients, and the hepatic artery, which delivers oxygenated blood to the liver.¹⁷ The interstitium is covered by a dense connective tissue capsule that extends into the parenchyma, dividing the liver into many lobules. Hepatocytes exhibit different functions and organelle characteristics depending on their position along the portal-central vein axis.¹⁸ Peri-portal hepatocytes show higher levels of oxidative phosphorylation and enhanced fatty acid β-oxidation, while peri-central vein hepatocytes are enriched in glycolysis and primarily focused on lipid synthesis.^19,20 This partitioning reflects spatial differences in mitochondrial structure and function, highlighting the heterogeneity of mitochondrial function and structure across liver regions. The walls of the sinusoids are composed of porous sinusoidal endothelial cells containing Kupffer cells and lymphocytes. Between the endothelial cells and hepatocytes lies a narrow Disse lumen containing hepatic stellate cells.²¹ Under physiological conditions, hepatocytes maintain the oxygen/redox gradient, regulate lipid metabolism, and balance energy throughout the liver lobules. However, chronic metabolic overload disrupts this regional distribution, with significant regional-specific changes in triglycerides, diglycerides, sphingolipids, and ceramides, redistributing from the peri-central venous region to the peri-portal venous region, and increased fibrosis in the peri-portal venous region.²² Excessive ROS production, mitochondrial depolarization, and impaired adaptive biosynthesis occur, particularly in hepatocytes prone to lipid accumulation and oxidative stress.²³

Under stress, hepatocyte mitochondria release mitochondrial damage-associated molecular patterns (mito-DAMPs), including oxidized mitochondrial DNA (mtDNA), cardiolipin, and N-formyl peptide.²⁴ Due to the structural similarity of mtDNA to bacterial DNA, it can act as a pattern recognition receptor and an endogenous ligand for the cyclic GMP-AMP synthase (cGAS)-STING pathway, activating NF-κB, IRF3, and downstream pro-inflammatory cytokines,^25,26 thereby linking hepatocyte mitochondrial stress to NAFLD/NASH. Mitochondrial release of mitochondrial DAMPs from damaged hepatocytes directly activates hepatic stellate cells, the fibroblasts in the liver, and drives liver scarring.²⁷ Conversely, innate immune cells within the hepatic sinusoids, particularly Kupffer cells, can recognize leaked mtDNA via TLR9 and STING, promoting macrophage polarization toward a pro-inflammatory M1 phenotype and enhancing cytokine production.²⁸

In summary, MASLD is a disease characterized by dysregulation of liver-mitochondrial interactions, in which regional mitochondrial dysfunction alters hepatocyte metabolic progression. A deeper understanding of the mechanisms of this bidirectional interaction is crucial for developing organelle-targeting therapies.

Mitochondrial Dysfunction and Quality Control Failure in MASLD

Mitochondrial dysfunction lies at the core of MASLD. Hepatic lipid overload, oxidative stress, and organelle crosstalk collectively impair mitochondrial bioenergetics, dynamics, and turnover. Instead of a vague “mitochondrial dysfunction,” MASLD is now understood as a progressive collapse of MQC encompassing mitochondrial genetics, calcium homeostasis, dynamics, mitophagy, biogenesis, and proteostasis.

Mitochondrial Genetics

mtDNA is a small circular genome located in the mitochondrial matrix that encodes 13 essential polypeptides of the oxidative phosphorylation (OXPHOS) system, as well as 2 rRNAs and 22 tRNAs required for translation within mitochondria.²⁹ The functional integrity of mtDNA is fundamental to the normal assembly of oxidative phosphorylation complexes, ATP production, and mitochondrial bioenergetics.³⁰ Unlike nuclear DNA, mtDNA lacks protective histones and has limited DNA repair capabilities, making it more susceptible to oxidative damage and mutations during physiological and pathological oxidative stress.³¹ The proximity of mtDNA to the electron transport chain (ETC) and its relatively inefficient base excision repair mechanism make mtDNA more susceptible to oxidative base damage, strand breaks, point mutations, and deletions.^32,33

Lipid Accumulation

Hepatic lipid overload occurs when the balance between lipid uptake and clearance is disrupted. Insulin resistance in adipose tissue and the liver is a key factor leading to metabolic imbalance in MASLD. Excess free fatty acids (FFAs) produced by diet and adipose tissue are not only stored in lipid droplets as triglycerides (TG),³⁴ but also give rise to lipid intermediates such as saturated fatty acids, diacylglycerols (DAG), sphingosine/sphingomyelin, and free cholesterol. These metabolites interfere with insulin signaling, activating inflammatory and pro-apoptotic pathways.^35,36 Hyperinsulinemia upregulates de novo lipid synthesis (DNL) in hepatocytes while restricting very low-density lipoprotein (VLDL) secretion, thereby providing lipogenic substrates.³⁷ This lipid burden forces excessive mitochondrial β-oxidation.

ROS Production

Excessive β-oxidation of fatty acids leads to an overproduction of reducing NADH and FADH₂, which overloads the mitochondrial ETC. Because the ETC has limited capacity, this results in over-reduction of electron carriers, particularly at Complex I and III, causing electrons to leak prematurely and react with oxygen to form mitochondrial reactive oxygen species (mtROS), such as superoxide and hydrogen peroxide.^6,38 Elevated mtROS levels damage respiratory chain complexes, mitochondrial membranes, and mitochondrial DNA, impairing electron transport and weakening the proton gradient, ultimately reducing OXPHOS efficiency and ATP production.³⁹ In the livers of NAFLD mice, increased markers of mitochondrial autophagy, decreased mitochondrial respiratory chain complex activity, and reduced ATP content were associated with defects in oxidative phosphorylation subunits.⁴⁰ mtDNA mutations, particularly in the MT-CYB gene encoding Complex III core subunit, are associated with advanced NASH, metabolic disorders, and biomarkers of oxidative damage.⁴¹ It also oxidizes inner-membrane lipids and damages respiratory-chain proteins, as shown in diet-induced NAFLD mouse models, which exhibit decreased stability and activity of multiple oxidative phosphorylation subunits, including complexes I and IV.⁴²

Inflammation

Excessive mtROS, together with endoplasmic reticulum (ER) stress, activate stress-responsive signaling pathways, including c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB), thereby initiating pro-inflammatory transcriptional programs.⁴³ Simultaneously, mitochondrial damage leads to the release of mtDAMPs, particularly oxidized mtDNA, into the cytoplasm and extracellular space. These mtDAMPs stimulate the NLRP3 inflammasome, thereby exacerbating liver inflammation and driving metabolic reprogramming.¹⁸ In addition, mitochondrial DNA released into the cytosol can activate the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway, further linking mitochondrial damage to innate immune activation and type I interferon responses.⁴⁴ Clinical studies have confirmed that reduced mtDNA copy number and base deletions in the livers of MASLD patients, as well as mitochondrial DNA copy number and deletion levels, may affect susceptibility to non-alcoholic fatty liver disease.¹⁵ Mitochondrial genome sequencing of livers from NAFLD patients revealed increased mutation rates and heterogeneity, particularly in genes encoding ETC proteins, with more severe disease phenotypes exhibiting higher mtDNA variant loads.⁴⁵

Fibrosis

Persistent mitochondrial dysfunction and unresolved inflammation ultimately drive the progression from steatosis to fibrosis. A central event in fibrogenesis is the activation of hepatic stellate cells (HSCs), which transdifferentiate into myofibroblast-like cells in response to inflammatory and oxidative cues.⁴⁶ mtROS and oxidized mtDNA contribute to this process both directly and indirectly. On the one hand, ROS promotes transforming growth factor-β (TGF-β) signaling, a master regulator of fibrogenesis, thereby enhancing collagen synthesis and extracellular matrix (ECM) deposition.⁴⁷ On the one hand, ROS promotes transforming growth factor-β (TGF-β) signaling, a master regulator of fibrogenesis, thereby enhancing collagen synthesis and ECM deposition. On the other hand, mtDNA-mediated activation of innate immune pathways, NLRP3 and cGAS–STING, sustains a pro-fibrotic inflammatory milieu.⁴⁸ Increased mtDNA mutation loads correlate with more severe fibrosis stages in NASH patients.^41,45

These changes impair ATP synthesis, lead to the continuous production of ROS, and create a self-reinforcing cycle of oxidative damage (Figure 1). This mitochondrial genetic instability is an early and crucial pathological change in the progression of MASLD.

Figure 1 Integrated mitochondrial quality control failure drives the progression of MASLD from lipid overload to inflammation and fibrosis.

Mitochondrial Calcium Dysregulation

Under physiological conditions, intracellular calcium (Ca²⁺) acts as a dynamic second messenger that regulates mitochondrial metabolism, ATP production, and cell fate decisions.⁴⁹ In healthy hepatocytes, the functional contact between the ER and mitochondria is called the mitochondrial-associated endoplasmic reticulum membrane (MAMs), and mitochondrial Ca²⁺ levels are strictly regulated by MAMs.⁵⁰ Ca²⁺ is pumped from the ER into the mitochondrial matrix through molecular complexes such as the IP₃ receptor (IP₃R), GRP75, and voltage-dependent anion channels (VDACs).^51–53 Ca²⁺ overload activates key dehydrogenases in the tricarboxylic acid cycle, enhancing oxidative phosphorylation capacity.⁵⁴ Normal Ca²⁺ cycling thus maintains energy homeostasis and prevents undue oxidative stress. In MASLD, mitochondrial dysfunction is associated with ER stress, organelle contact signaling, and programmed cell death. Chronic ER stress leads to Ca²⁺ dys-homeostasis at MAMs, where excessive ER-to-mitochondria Ca²⁺ transfer triggers mitochondrial Ca²⁺ overload, enhanced mtROS production, and further ER dysfunction.⁵⁵ Both clinical and animal studies have confirmed that in NAFLD, lipid overload and persistent ER stress promote mitochondrial Ca²⁺ overload.⁵⁶ Hepatocellular ER stress and Ca²⁺ dysregulation promote JNK/NF-κB activation and NLRP3 inflammasome assembly, thereby converting organelle stress into sterile hepatic inflammation.⁵⁷ These inflammatory signals trigger multiple modes of regulated cell death, including apoptosis, necroptosis, and, particularly, ferroptosis, which is driven by mitochondrial lipid peroxidation and the production of iron-dependent reactive oxygen species.⁵⁸ Studies have found that inhibiting mitochondrial Ca²⁺ influx using Xestospongin-C can significantly reduce mtROS production and ER stress-induced damage responses, suggesting that Ca²⁺ overload and its downstream ROS signaling are key nodes connecting ER stress and mitochondrial dysfunction.⁵⁶ These organelle stress responses converge on mitochondria but affect distinct quality-control arms. Thus, disrupted Ca²⁺ signaling forms a crucial link between organelle stress, inflammation, and hepatocellular death in MASLD (Figure 2).

Figure 2 Dysregulation of Mitochondrial Calcium Homeostasis and Dynamics Drives Hepatocellular Stress and Metabolic Dysfunction in MASLD.

Mitochondrial Dynamics

Mitochondrial dynamics is primarily regulated by a series of characteristic fusion and splitting proteins, making it a structurally well-defined module within the MQC that can serve as a therapeutic target. Mitochondrial fusion is mediated by MFN1/2 on the outer mitochondrial membrane and optic atrophy protein 1 (OPA1) on the inner mitochondrial membrane, thereby enabling mitochondrial elongation, content mixing, and mtDNA complementarity. In hepatocytes, mitochondrial fusion maintains mitochondrial membrane potential, optimizes OXPHOS, and supports efficient fatty acid β-oxidation.⁵⁹ Conversely, mitochondrial division is primarily driven by dynein-associated protein-1 (DRP1),⁶⁰ which is recruited from the cytosol to the mitochondria via receptors such as FIS1, MFF, and MiD49/51.⁶¹ Fission facilitates mitochondrial distribution, quality control, and the selective removal of damaged organelles via mitophagy.^62,63

MFN2 not only regulates mitochondrial junctions and fusions but also acts as a receptor for PINK1-mediated Parkin recruitment, linking mitochondrial dynamics to mitophagy. MFN2 expression is significantly reduced in liver biopsy tissues from human non-alcoholic steatohepatitis (NASH); specific knockout of the MFN2 gene in mouse hepatocytes leads to triglyceride accumulation, endoplasmic reticulum stress, and inflammation.⁸ OPA1 is a dynamin-associated GTPase protein located in the inner mitochondrial membrane and is a key regulator of mitochondrial inner membrane fusion. OPA1 deficiency can activate ATF5-mediated UPR^mt and induce FGF21 expression, thereby improving systemic glucose homeostasis and protecting against diet-induced obesity and insulin resistance.⁶⁴ Gene knockout of OPA1 can prevent macromitochondrial formation and liver damage. Targeting OPA1 to block mitochondrial fusion can alleviate NASH pathology.⁶⁵

DRP1 overactivation promotes mitochondrial fragmentation, leading to loss of membrane potential, impaired ETC function, and increased mtROS production.⁶⁶ Clinical studies have confirmed that Drp1 expression gradually increases from NAFLD to NASH, then to NASH-related fibrosis, and finally to cirrhosis, and is mainly expressed in Kupffer cells.⁶⁷ The ketogenic diet reduces Fis1 and Drp1 levels, increases ATP levels, and increases key genes for fatty acid oxidation, improves mitochondrial dysfunction, alleviates lipid deposition, restores mitochondrial homeostasis, and improves mitochondrial dysfunction in the liver of MASLD mice.⁶⁸ Activation of DRP1/MFF induces excessive mitochondrial fission, inhibits Nrf2/HO-1, increases intracellular ROS, induces macrophage and liver inflammation, activates HSCs, leading to ECM deposition, and ultimately promotes liver fibrosis.⁶⁹ MiD49/51 can independently mediate DRP1 recruitment, independent of Fis1 and MFF. Targeting MiD49/51 may block fatty acid-induced abnormal mitochondrial fission, and combined targeting of MiD51 and MFF enhances the anti-fission effect.⁷⁰ The mitochondrial fission inhibitor Mdivi-1 can reduce mitochondrial ROS levels and decrease the expression of fibrosis markers.⁷¹

In summary, mitochondrial dynamics, comprising fusion and fission proteins, constitute the core regulatory axis of MASLD (Figure 2). Dysregulation of these proteins leads to mitochondrial dysfunction, metabolic stress, inflammation, and fibrosis, making them highly attractive targets for precision medicine strategies (Table 1).

Table 1 Expression Changes of Key Mitochondrial Dynamics Proteins in MASLD

Mitophagy and Lysosomal Clearance

Mitophagy removes dysfunctional mitochondria through selective recognition and lysosomal degradation. In MASLD, impaired mitophagy leads to the persistence of damaged organelles, exacerbating oxidative stress, lipid accumulation, inflammation, and fibrosis. Mitophagy mechanisms primarily occur through two pathways: a ubiquitin-dependent PINK1-Parkin pathway and a receptor-mediated pathway involving outer membrane proteins BNIP3, NIX, and FUNDC1.

PINK1–Parkin–dependent mitophagy is the primary pathway for tagging dysfunctional mitochondria. When membrane potential collapses, PINK1 accumulates on the outer membrane and recruits Parkin, which ubiquitinates multiple substrates to initiate autophagosome assembly.^72,73 Parkin overexpression reduces lipid accumulation and restores mitochondrial morphology.⁷⁴ Conversely, liver-specific Parkin deficiency impairs mitophagy, accelerates steatosis, promotes insulin resistance, and increases fibrosis.⁷⁵ In addition to the PINK1–Parkin axis, receptor‑mediated mitophagy provides an alternative mechanism for the selective removal of damaged mitochondria. Mitochondrial outer membrane proteins BNIP3, NIX (BNIP3L), and FUNDC1 contain LC3 interaction region (LIR) motifs, enabling them to directly bind to LC3 on the autophagosome membrane and promote the formation of autophagosomes around mitochondria.^76,77 Their deficiency reduces mitochondrial clearance, thereby exacerbating liver damage and steatosis.⁷⁸

Growth differentiation factor 15 (GDF15) is a circulating biomarker of mitochondrial stress and impaired mitophagy. Clinical studies have found that serum GDF15 is positively correlated with non-hepatic mitochondrial respiration in obese individuals, but negatively correlated in patients with liver fibrosis.⁷⁹ Circulating GDF15 levels in patients with MASLD are higher than in the control group, and GDF15 levels in the MASH subgroup are positively correlated with fibrosis.⁸⁰

Mitochondrial Biogenesis and NAD⁺/SIRT1 Axis

Mitochondrial biogenesis compensates for organelle loss and restores oxidative capacity after injury. PGC‑1α/SIRT1 axis constitutes the central transcriptional regulatory hub orchestrating this process. SIRT1 directly deacetylates and activates PGC-1α in hepatocytes, linking nutrient and redox status to mitochondrial transcriptional programs.^81,82 Activated PGC-1α regulates mitochondrial biosynthesis by co-activating nuclear transcription factors, particularly NRF1/2. These transcription factors subsequently induce the expression of nuclear-encoded mitochondrial genes, including mitochondrial transcription factor A (TFAM).⁸³ TFAM, along with mitochondrial transcription factors B1 and B2 (TFB1M and TFB2M), binds to mtDNA and regulates its transcription and replication. This coordinated transcriptional program ensures proper maintenance of mtDNA and promotes the expression of OXPHOS components, thereby maintaining mitochondrial bioenergetic function.⁸² Suppression or loss of hepatic PGC-1α reduces mitochondrial content, lowers fatty-acid oxidation, and promotes triglyceride accumulation.¹⁶ High-fat or Western diet feeding downregulates hepatic SIRT1–PGC-1α signaling, decreases mtDNA copy number, and exacerbates steatosis.⁸⁴ Proteomic mapping of NAFLD liver reveals reduced turnover and abundance of OXPHOS subunits, consistent with defective renewal of the mitochondrial pool.⁴⁰ Restoring the SIRT1–PGC-1α pathway increases mitochondrial biogenesis, enhances β-oxidation, and attenuates steatosis in vivo.⁸⁵ Pharmacological activation of PPARα/PGC-1α increases mtDNA content and reduces hepatic lipid and oxidative stress in preclinical NAFLD models.⁸⁶ Human biopsy studies further confirm reduced hepatic PGC-1α in MASH, and liver-specific Pgc-1α deletion promotes fibrosis and respiratory dysfunction in vivo.⁸⁷ Collectively, impaired biogenesis in MASLD represents a failure of mitochondrial regeneration, reducing functional organelle reserves and amplifying susceptibility to oxidative injury (Figure 3).

Figure 3 Regulation of Mitochondrial Biogenesis and Proteostasis via the NAD+/SIRT1 Axis and UPRmt Signaling in MASLD.

Mitochondrial Proteostasis and UPR^mt

Mitochondrial protein homeostasis encompasses the folding, assembly, and proteolytic clearance of mitochondrial proteins, and depends on molecular chaperones (HSP60/HSP10, mtHSP70), matrix proteases (ClpP, LONP1), and the mitochondrial unfolded protein response. Molecular chaperones HSP60/HSP10 and mtHSP70 constitute the first line of defense against mitochondrial protein misfolding. HSP60, a highly conserved molecular chaperone, works in concert with its co-chaperone HSP10 to facilitate the folding and assembly of newly imported precursor proteins into their native conformations within the mitochondrial matrix,⁸⁸ while matrix proteases, such as the LONP1 and ClpXP complex (ClpP/ClpX), clear irreversibly damaged or misfolded proteins.^89,90 Emerging evidence indicates that aberrant HSP expression and function contribute to NAFLD pathogenesis. In liver irritation from diet or toxins, HSP60 and LONP1 are upregulated, thereby maintaining OXPHOS assembly and limiting acute mtROS expansion. LONP1 controls PINK1 processing and thus modulates mitophagy initiation.⁹¹ Upregulation of LONP1 can improve mitochondrial structure and function in a fatty liver model.⁹² In both MASH patients and high-fat diet-induced MASH mouse models, the expression of LONP1 in hepatocytes was significantly reduced, and this reduction was closely related to the degree of liver fibrosis.⁹³ ClpP abundance affects OXPHOS subunit turnover.⁹⁴ Recent studies further reveal that LONP1 collaborates with mtHSP70 to couple folding surveillance with degradation decisions.⁹⁵ In patients with NASH and mice, MRG15 levels are elevated in the liver. TUFM deacetylation is accelerated by the mitochondrial ClpXP protease system, leading to impaired mitophagy, increased oxidative stress, and activation of the NLRP3 inflammasome pathway.⁹⁶

UPR^mt is a nuclear-driven transcriptional program that upregulates these effector factors when mitochondrial protein toxicity stress accumulates.⁹⁷ With persistent metabolic overload, however, UPR^mt can become maladaptive. Chronic elevation or dysregulation of proteases/chaperones associates with mitochondrial swelling, defective β-oxidation, and inflammatory priming in NASH.⁹⁸ NAD⁺ repletion and redox modulators restore components of UPR^mt (HSP60/ClpP/LONP1), improve OXPHOS assembly, and reduce steatosis or toxin-induced injury in animal and cell models.⁹⁹ UPR^mt-induced FGF21 secretion is significantly enhanced during early UPRmt activation and declines in late disease stages due to excessive lipid deposition.¹⁰⁰ Functionally, FGF21 exerts a pleiotropic protective effect by promoting autophagy and mitochondrial respiration while inhibiting lipogenesis, glucose production, inflammation, and fibrosis signaling, thereby reducing metabolic stress and promoting fibrosis regression in MASLD.¹⁰¹

Natural Products Targeting MQC in MASLD: Molecular Mechanisms and Pharmacology

Natural Products Modulating Mitochondrial Dynamics

MFN1/2 and OPA1 primarily mediate mitochondrial fusion, whereas fission is orchestrated by DRP1 and mitochondrial fission protein 1 (FIS1). Loss of MFN2 has been causally linked to hepatic steatosis, ER stress, and progression to NASH.⁸ Conversely, DRP1 is a crucial player in mitochondrial fission and liver function. Its deficiency alters inter-organelle communication, enhancing mitochondria lipid droplet and ER mitochondria lipid droplet contacts while weakening mitochondria ER lipid droplet interactions.¹⁰² Several natural compounds have been shown to restore mitochondrial dynamic equilibrium, thereby mitigating lipid accumulation and oxidative injury in NAFLD models.

Oroxylin A, a flavonoid, can upregulate the expression of the MFN2 transcriptional coactivator PGC-1α, thereby enhancing MFN2 expression and promoting mitochondrial fusion, improving lipid deposition, and inhibiting excessive mitochondrial ROS production.¹⁰³ Similarly, hesperetin, a flavanone glycoside, decreases Drp1 and its phosphorylated forms (Drp1-pS616, Drp1-pS637), as well as mitophagy-related proteins (PINK1, Parkin), while increasing MFN2 and OPA1 levels, thereby favoring mitochondrial fusion and improving cellular redox balance.¹⁰⁴ Dihydromyricetin, a dihydroflavonol, improves mitochondrial structure, restores membrane potential, and rebuilds fusion-fission balance by enhancing antioxidant enzyme activity, scavenging ROS, and regulating the expression of key mitochondrial dynamic proteins (Mfn1/2, Opa1, Drp1, Fis1).¹⁰⁵ Likewise, Rutin, a flavonol glycoside, attenuates hepatic steatosis by suppressing DRP1, inhibiting excessive mitochondrial fission, and promoting mitochondrial functional recovery and cell viability.¹⁰⁶

Peanut Shell Extract has also been reported to normalize mitochondrial homeostasis in diabetic mice, as evidenced by reduced hepatic DRP1, PINK1, and TNFα levels, alongside elevated MFN1, MFN2, OPA1, TFAM, PGC-1α, and NRF2 expression.¹⁰⁷ Peanut shell extract is primarily composed of Flavonoids, Phenolic acids, and General polyphenolic antioxidants.¹⁰⁸ Astaxanthin, a Carotenoid, downregulates ER stress–related genes (GRP94, GRP78, ATF4, ATF6, PERK, eIF2α, IRE1, CHOP) and rebalances mitochondrial dynamics by inhibiting fission (DRP1, Mff) and promoting fusion (OPA1, MFN1, MFN2).⁶³ Diosgenin, a Steroidal saponin aglycone, exerts hepatoprotective effects by modulating the PERK and IRE1 branches of the unfolded protein response (UPR), thereby reducing ER stress and de novo lipogenesis. It concurrently inhibits DRP1 and upregulates MFN1/MFN2, mitigating mitochondrial dynamic disruption in NAFLD.¹⁰⁹ In contrast, bavachin, a Flavonoid, exacerbates hepatic injury by activating DRP1-mediated excessive mitochondrial fission and ER stress–related apoptosis through the Wnt/β-catenin signaling pathway, highlighting the detrimental impact of unrestrained fission activity.¹¹⁰

Collectively, these findings underscore the pivotal role of mitochondrial dynamics as a therapeutic target in NAFLD. Natural products that promote mitochondrial fusion, inhibit excessive fission, and alleviate ER stress may provide multifaceted protection by restoring mitochondrial integrity, suppressing oxidative stress, and improving hepatocellular metabolism (Table 2).

Table 2 Representative Natural Products Targeting MQC in MASLD

Natural Products Enhancing Mitophagy

Mitophagy failure represents a central metabolic vulnerability in MASLD, in which impaired PINK1 stabilization, defective Parkin recruitment, and redox overload converge to impede mitochondrial turnover. Many natural products can activate the PINK1/Parkin pathway, reduce mitochondrial reactive mtROS levels, restore membrane potential, and protect hepatocytes from lipotoxicity. Cyanidin-3-O-glucoside promotes AMPK activation, increases PINK1 and Parkin expression, and enhances mitophagy. This facilitates the removal of damaged mitochondria and lowers mitochondrial ROS in ethanol-injured hepatocytes.¹¹⁴ Corilagin restores autophagic flux in HFD-fed mice. It increases LC3-II levels, enhances LC3–Parkin colocalization with mitochondria, elevates mitophagosome formation, and reduces mtROS. These changes restore mitochondrial membrane potential (Δψm) and attenuate steatosis and oxidative injury.¹²⁷ Quercetin also downregulates autophagy-related genes (ATG5, ATG7, Beclin-1, LC3A/B) and necroptosis-related genes (Fas, Bcl-2, Drp1, RIPK1), reducing LC3-I, LC3-II, and the LC3-II/LC3-I ratio.¹¹¹ It further increases PINK1, Parkin, BNIP3, and LC3-II, and reduces p62, TOM20, and VDAC1.¹¹² Baicalin and its nanoliposome rescue ΔΨm and reduce oxidative stress. They activate PINK1/Parkin-dependent mitophagy, clear damaged mitochondria, and restore mitochondrial function in toxin-induced liver injury.¹²⁸ Sesamin and corn peptides activate PINK1/Parkin-mediated mitophagy in HepG2 cells. They increase mitochondrial autophagy, improve mitochondrial homeostasis, enhance fatty acid metabolism, and reduce lipid accumulation.^129,130 These studies reveal a common mechanism: Parkin translocation restoration, reduction of mtROS, and restoration of membrane potential.

Although the PINK1/Parkin pathway dominates the literature, some natural products can also activate the BNIP3, FUNDC1, and pyroptosis-related mitophagy pathways. Ginsenoside Rb1 activates PINK1/Parkin-dependent mitophagy, reduces mtROS, suppresses NLRP3 activation, and limits pyroptosis in immune-injured hepatocytes.^116,131 Ginsenoside Rg1 stabilizes Δψm and triggers mitophagy via the same pathway, protecting liver tissue during ischemia-reperfusion.¹³² Punicalagin intervention significantly increased the expression of Pink1, Parkin, Bnip3, LC3b, and P62 in the liver, and significantly increased MMP. It reduced oxidative stress in the liver by upregulating mitophagy and antioxidant enzyme activity, thereby exerting a protective effect against diabetic liver injury.¹¹⁵ These findings expand the field beyond PINK1/Parkin by showing that natural products can also modulate BNIP3, FUNDC1, and inflammasome–mitochondria crosstalk.

AMPK acts as a metabolic rheostat coupling nutrient signals with MQC. Several compounds stimulate mitophagy by rewiring hepatocellular energy sensing. Quercetin reduces intracellular lipids and ROS/DHE, upregulates PINK1/Parkin signaling, clears damaged mitochondria, and improves hepatic lipid metabolism, thus preventing NAFLD through AMPK-mediated mitophagy.¹¹³ Cajaninstilbene Acid increased the expression of PGC-1α, TFAM, LC3-II, PINK1, and mitochondrial Parkin, and decreased p62 expression. It alleviated APAP-induced oxidative stress and enhanced mitochondrial quality control by activating Sestrin2/AMPK.¹³³

Some natural products act upstream by strengthening antioxidant defenses or deacetylation networks, creating a cellular environment permissive for efficient mitophagy. Resveratrol has anti-inflammatory, antioxidant, and detoxifying properties. It upregulates PINK1, Parkin, Beclin-1, LC3B, and ATG5, while lowering p62.¹¹⁷ Resveratrol also restores Parkin-mediated mitophagy in acute CCl₄ injury by elevating PINK1, Parkin, and LC3-II, reducing p62, and limiting lipid peroxidation and apoptosis.¹¹⁸ In fish hepatocytes, resveratrol activates SIRT1/PGC-1α and PINK1/Parkin pathways, reduces ROS, and suppresses NF-κB, thereby promoting mitochondrial clearance and biogenesis.¹¹⁹ Polydatin activates SIRT3-FOXO3-BNIP3 and PINK1-PRKN pathways. It enhances mitochondrial autophagy, improves mitochondrial biogenesis, and corrects hepatic injury and steatosis in NAFLD mice and hepatocytes.¹²¹ Korean Red Ginseng increases PINK1 and Parkin expression, enhances mitophagy, improves insulin signaling, and reduces oxidative stress in hepatocytes under metabolic stress.¹³⁴ Salidroside increases PINK1, Parkin, and LC3-II, and decreases Bax/Bcl-2 and p62. These changes maintain mitochondrial function and prevent hepatocyte injury.¹³⁵

Collectively, these compounds converge on a unifying mechanism: restoring the mitophagy–biogenesis equilibrium as a foundational strategy to correct lipotoxicity, oxidative stress, and hepatocellular dysfunction in MASLD (Table 2).

Natural Products Promoting Mitochondrial Biogenesis and NAD⁺ Metabolism

Mitochondrial biogenesis is crucial for maintaining MQC and energy homeostasis. PGC‑1α acts as a master transcriptional coactivator, driving mtDNA replication and mitochondrial protein expression. Several natural products have been reported to promote mitochondrial biogenesis through various upstream signaling pathways.

Several compounds act primarily by coupling AMPK/PGC-1α, reactivating the canonical metabolic stress response. Luteolin stimulates mitochondrial biogenesis via the AMPK/PGC‑1α pathway, increasing mitochondrial mass and ATP production in hepatocytes.¹²² Picrorhiza kurroa upregulates PGC‑1α, TFAM, and Nrf2, promoting mitochondrial biogenesis while exerting anti-inflammatory and anti-fibrotic effects.¹³⁶ Resveratrol enhances the PGC‑1α/PPARγ axis, increases mtDNA copy number and biogenesis-related proteins, and restores hepatocyte energy metabolism.¹²⁰ Oleuropein increases LKB1/PGC‑1α promoter binding, upregulates PGC‑1α and TFAM expression, and suppresses hepatic lipogenesis, linking mitochondrial biogenesis to improved lipid metabolism.¹²³ These findings suggest that natural compounds can simultaneously enhance mitochondrial function and combat steatosis by activating AMPK.

SIRT1, a NAD⁺-dependent deacetylase, a growing cluster of natural products restores mitochondrial biogenesis by re-establishing NAD⁺ metabolism and SIRT1/3 activity. Lycium ruthenicum polysaccharides activate SIRT1/PGC‑1α signaling, maintaining mitochondrial structure and function, improving ATP levels, and reducing oxidative stress in liver injury models.¹³⁷ Astragaloside IV activates PGC‑1α, AMPK, and SIRT3 in AML12 hepatocytes, promoting mitochondrial biogenesis and exerting antioxidative effects.¹²⁴ Curcumin activates SIRT3, increases mtDNA copy number and superoxide dismutase activity, and improves mitochondrial respiration in fatty hepatocytes.¹³⁸ Bergenin upregulates SIRT1 and activates the AMPK/SIRT1 axis, stimulating hepatic mitochondrial biogenesis.¹³⁹ Baicalein regulates the AMPK/SIRT1/PGC‑1α pathway, modulating mitochondrial biogenesis and dynamics, and attenuates macrophage M1 hyperpolarization and hepatocyte pyroptosis via NF‑κB inhibition.¹⁴⁰ Restoring NAD⁺ sirtuin tone is a prerequisite for sustained mitochondrial biogenesis in metabolic liver diseases.

Several agents enhance mitochondrial biogenesis indirectly by remodeling autophagy–lysosome signaling, expanding the mechanistic diversity of natural-product interventions. The rhizome of Gentiana kurroo is dominated by secoiridoid glycosides, supported by xanthones, flavonoids, and phenolics.¹⁴¹ Gentiana kurroo rhizome improves hepatic ADH, SREBP1c, and mitochondrial biogenesis gene expression, reduces lipid peroxidation, and enhances antioxidant enzyme activities.¹⁴² Hyperoside inhibits mTORC1, activating the TFEB-mediated autophagy-lysosome pathway and mitochondrial biogenesis, alleviating palmitic acid-induced liver injury.¹⁴³

Some natural products activate both mitochondrial biogenesis and mitophagy. Lycium barbarum polysaccharide (LBP) administration reduces oxidative stress, restores mitochondrial structure and function, and prevents mitochondrial dysfunction, thereby mitigating hepatic fibrosis.¹⁴⁴ Another study demonstrated that LBP enhances mitochondrial respiration, increases tissue ATP levels, and reactivates respiratory chain complexes I–V, alleviating mitochondrial damage and boosting hepatic antioxidant capacity.¹⁴⁵ Cordycepin promotes Parkin-dependent mitophagy and mitochondrial biogenesis, restoring mitochondrial homeostasis and reducing oxidative stress, thereby alleviating MASLD.¹⁴⁶ Pseudolaric Acid B upregulates PPARα downstream genes involved in lipid metabolism and mitochondrial biogenesis, reduces lipid accumulation, improves liver injury, and enhances mitochondrial biogenesis.¹⁴⁷

In summary, Natural products do not merely increase mitochondrial number; they reprogram mitochondrial quality, redox homeostasis, and metabolic signaling through convergent activation of PGC-1α, sirtuins, and nuclear transcription factors. This mechanistic convergence highlights mitochondrial biogenesis, not as an isolated compensatory response, but as a central therapeutic axis that integrates lipid metabolism, inflammation, autophagy, and NAD⁺ biology (Table 2).

Natural Products Improving Mitochondrial Proteostasis and UPR^mt

Direct evidence that natural products modulate canonical UPR^mt components in liver disease models remains sparse but is emerging. Hesperidin has a potential binding site for SIRT3, thereby activating the SIRT3-FOXO3A signaling pathway and leading to a significant decrease in the expression levels of UPR^mt-related proteins and genes.¹⁴⁸ Nicotinamide riboside can alleviate ethanol-induced oxidative stress, inflammation, and mitochondrial dysfunction, and regulate the ATF5-dependent UPR^mt pathway in ImKCs.¹²⁵ Nicotinamide riboside also increases the expression of UPR^mt markers, including ClpP and HSP60, and restores mitochondrial protein homeostasis and function in preclinical studies, providing a feasibility for drug-induced UPR^mt.¹²⁶ Lipoic acid can regulate UPR^mt and alleviate oxidative stress, reducing UPRmt activation induced by a FFA mixture in HepG2 cells while improving mitochondrial function.⁹⁹ Despite mechanistic plausibility and a few promising reports, several critical gaps remain. Few liver studies measure the full UPR^mt signature after natural-product treatment. How UPR^mt interacts temporally with mitophagy, fusion/fission, and biogenesis under natural-product treatment remains largely untested (Table 2).

Multi-Target MQC Modulation by Traditional Chinese Medicine Formulas

Unlike single-target small molecules, TCM formulas frequently act on coordinated mitochondrial modules, enabling integrated remodeling of hepatocellular metabolism. Several formulas simultaneously promote mitochondrial biogenesis and stabilize mitochondrial structure. Jianpi Shengqing Huazhuo Formula promotes liver mitochondrial biosynthesis, improves glucose and lipid metabolism, and regulates the mitochondrial-dependent apoptosis marker Bcl-2/Bax to alleviate liver damage.¹⁴⁹ The modified Rougan decoction upregulates the SIRT1/PGC-1α pathway to promote mitochondrial biosynthesis, maintain mitochondrial structure and function, and thus reduce hepatocyte apoptosis.¹⁵⁰ TCM formulas frequently modulate mitochondrial dynamics and their coupling to mitophagy. Sheng Mai San regulates glycolysis and the tricarboxylic acid cycle to support energy metabolism, promotes AMPK phosphorylation, and maintains mitochondrial homeostasis, thereby alleviating liver damage through Drp1-dependent mitophagy.¹⁵¹ GerGen-ChynLian-Tang promotes Parkin-dependent, non-disintegrative mitophagy through mitochondrial fusion rather than fission.¹⁵²

Activation of mitophagy is a central and conserved signature across numerous formulas. Lipi Jiangzhuo Decoction increases the expression of PINK1 and Parkin proteins, increases the number of mitophagosomes, and restores mitochondrial membrane potential to activate mitophagy, reduces PERK expression to inhibit endoplasmic reticulum stress, improves liver function, and reduces liver lipid droplet accumulation.¹⁵³ S100A9/RAGE pathway activation impairs mitophagy, and the expression of Pink1, Parkin, and LC3B decreases. JianPi LiShi YangGan Formula increases the expression levels of Pink1, Parkin, and LC3B and enhances mitophagy, while inhibiting the activation of the S100A9/RAGE signaling pathway.¹⁵⁴ YangGan-JiangMei formula promotes PINK1/Parkin-mediated mitophagy and inhibits NLRP3 inflammasome activation, leading to recovery of mitochondrial function and reducing liver damage and lipid deposition.¹⁵⁵ Qidan Tiaozhi capsule activates AMPK/PINK1-Parkin-mediated mitophagy, thereby inhibiting oxidative stress and reducing intracellular lipid accumulation, as well as TC, TG, MDA, and ROS levels, and increasing SOD levels and mitochondrial membrane potential.¹⁵⁶

Traditional Chinese medicine formulas demonstrate their multi-component, multi-pathway pharmacological effects by systematically regulating multiple MQC levels, including mitochondrial dynamics, biosynthesis, mitophagy, and protein homeostasis (Table 3).

Table 3 Traditional Chinese Medicines for MASLD Mitochondrial Quality Control

Toxicology, Safety, and Translational Perspectives

Natural products can simultaneously activate mitophagy, stabilize mitochondrial dynamics, and enhance biosynthesis, making them useful for treating MASLD. However, their toxicological risks are often overlooked, as many drugs can impair mitochondrial function and lipid homeostasis.^158,159 Many traditional Chinese medicines and their active ingredients exhibit hepatotoxicity and nephrotoxicity under specific conditions. These toxicities are triggered by mechanisms such as ETC inhibition, ROS amplification, or membrane uncoupling, posing a significant obstacle to their translational application.¹⁶⁰ MASLD hepatocytes are characterized by redox overload and impaired MQC buffering capacity, which exacerbates their susceptibility to toxic metabolites and membrane depolarization.¹⁶¹ The toxic components of Evodiae Fructus and Polygonum multiflorum or their metabolic intermediates can induce excessive mitochondrial ROS production, disrupt mitochondrial membrane potential, and inhibit oxidative phosphorylation, leading to insufficient ATP synthesis, activation of mitochondrial permeability transition and cell death pathways, and exacerbating hepatocyte damage.^162,163 Furthermore, many natural products, such as Emodin, have low bioavailability,¹⁶⁴ complex metabolic activation, and inter-individual variability in metabolism influenced by the gut microbiota,^165,166 further complicating their translational applications. Advanced formulations (nanoparticles, liposomes) improve exposure but may alter subcellular targeting and mitochondrial distribution, creating new uncertainties.¹⁶⁷ In summary, natural products possess significant potential to modulate the MQC network in MASLD. To drive the clinical translation of MQC-targeted natural products, key research areas include subcellular pharmacokinetics, standardized mitophagy and respiratory flux assays, and the development of MQC-related biomarkers. Formulation innovation should focus on targeted delivery systems to minimize systemic toxicity.

Conclusions and Perspectives

MASLD is a disease characterized by hepatic lipid metabolism imbalance, driven not only by metabolic overload but also by mitochondrial quality-control failure. MASLD is not a single “mitochondrial dysfunction,” but rather is characterized by selective and progressive damage to different MQC modules, including excessive cell division, defective mitophagy, insufficient biosynthesis, and dysregulation of protein homeostasis. These defects collectively impair hepatocytes’ resistance to chronic nutritional stress. Importantly, these mitochondrial defects exhibit a spatial distribution within liver lobules and spread beyond hepatocytes via the inflammatory and fibrotic signaling pathways, mediated by mitochondrial DAMP.

Natural products, as a unique class of drugs, can target this multifaceted MQC network. Unlike single-pathway drugs, many natural compounds and traditional Chinese medicine formulas can simultaneously activate the AMPK-SIRT-PGC-1α-driven biosynthetic pathway, restore PINK1/Parkin-dependent mitophagy, rebalance mitochondrial dynamics, and regulate the UPR^mt signaling pathway, thereby reprogramming mitochondrial quality rather than simply increasing mitochondrial quantity. This systemic regulation is closely related to the complex multi-hit pathogenesis of MASLD.

However, clinical translation still faces many challenges. The hepatotoxicity, limited bioavailability, and context-dependent effects of natural products on mitochondria necessitate rigorous toxicological assessments, subcellular pharmacokinetic analyses, and standardized MQC biomarker assays. These advances will make mitochondrial quality control an actionable and drug-targetable axis in the precision treatment of MASLD.