Endoplasmic Reticulum-Targeting Natural Compounds: A Novel Frontier in Alleviating Liver Fibrosis

Chengrong Huang; Wei Hu; Jia Qi; Bolun Su; Hongrui Yan; Yi Zhun Zhu

doi:10.2147/DDDT.S564440

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Review

Endoplasmic Reticulum-Targeting Natural Compounds: A Novel Frontier in Alleviating Liver Fibrosis

Authors Huang C, Hu W, Qi J, Su B, Yan H, Zhu YZ

Received 1 September 2025

Accepted for publication 5 December 2025

Published 23 December 2025 Volume 2025:19 Pages 11465—11482

DOI https://doi.org/10.2147/DDDT.S564440

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Tamer Ibrahim

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Chengrong Huang,^1,^2,^* Wei Hu,^1,^2,^* Jia Qi,³ Bolun Su,² Hongrui Yan,² Yi Zhun Zhu^1,²

¹School of Pharmacy, Macau University of Science and Technology, Macau SAR, 999078, People’s Republic of China; ²Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Macau SAR, 999078, People’s Republic of China; ³Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yi Zhun Zhu, Email [email protected]

Abstract: Liver fibrosis, a reversible yet critical stage in chronic liver disease progression, poses a significant global health burden with limited therapeutic options. This review comprehensively explores the molecular mechanisms of endoplasmic reticulum (ER) stress and its dual role in both parenchymal and non-parenchymal cells during liver fibrosis, alongside the therapeutic potential of natural compounds that target ER stress to alleviate fibrosis. Emerging evidence underscores ER stress and oxidative stress as pivotal drivers of hepatic fibrogenesis, primarily through activating hepatic stellate cells (HSCs). We systematically summarize a wide array of natural compounds, from polyphenols to terpenoids, that demonstrate potent anti-fibrotic effects by either ameliorating maladaptive ER stress in hepatocytes or selectively inducing pro-apoptotic ER stress in activated HSCs. Despite their promise, the clinical translation of these compounds is hampered by poor bioavailability and non-specific targeting. We highlight the groundbreaking potential of biomimetic nano-delivery systems, such as cell membrane-camouflaged nanoparticles, to overcome these barriers, offering precise targeting and enhanced therapeutic efficacy. Finally, we discuss current challenges and future directions, advocating for interdisciplinary efforts to advance ER stress-targeting strategies from bench to bedside.

Keywords: liver fibrosis, endoplasmic reticulum stress, unfolded protein response, natural compounds, targeted therapy

Introduction

Liver fibrosis is a pathological repair process triggered by chronic liver disease, characterized primarily by the excessive accumulation or abnormal distribution of extracellular matrix (ECM) components within the space of Disse.¹ Liver fibrosis is typically caused by a various of etiological factor, including viral infections,² metabolic abnormalities,³ alcohol use disorders,⁴ cholestasis,⁵ and autoimmune liver diseases.⁶ Additionally, long-term use of certain medications such as methotrexate, methyldopa, chlorpromazine, and tolbutamide has also been identified as a contributing factor to the progression of fibrosis.^7–9 Without effective intervention, liver fibrosis may advance to cirrhosis or even hepatocellular carcinoma, posing a significant global health burden. According to the most recent Global Burden of Disease data, liver cirrhosis led to over 1.4 million deaths globally in 2021, with the global incidence having increased by 58% between 1990 and 2021, highlighting a growing challenge.¹⁰ Currently, treatments targeting the underlying causes, for example antiviral therapies for hepatitis B or C, can partially reverse fibrosis.^11,12 Despite advancements in diagnostic techniques and therapeutic strategies, current treatments remain limited in efficacy, underscoring the urgent need for the development of novel anti-fibrotic therapies as a critical medical challenge.

Among the complex mechanisms driving liver fibrosis, endoplasmic reticulum (ER) stress has emerged as a pivotal contributor.¹³ Specifically, disruption of ER function triggers the unfolded protein response (UPR), which is a cellular stress response aimed at restoring ER homeostasis. However, under prolonged stress conditions, chronic ER stress leads to the sustained activation of UPR signaling pathways, ultimately resulting in inflammation, oxidative stress, and apoptosis.¹⁴ Notably, these processes play a central role in the activation of HSCs, the primary effector cells responsible for ECM deposition and fibrogenesis.¹⁵ Consequently, targeting ER stress has garnered significant attention as a promising therapeutic strategy for liver fibrosis.

Natural compounds have gained prominence in drug discovery and development due to their structural diversity, broad biological activities, and favorable safety profiles.¹⁶ Unlike synthetic drugs, many natural compounds exhibit lower toxicity and higher biocompatibility, making them attractive candidates for the treatment of chronic diseases. Recent studies have identified several natural compounds, such as curcumol, resveratrol, and chrysophanol, that mitigate ER stress by modulating UPR signaling pathways, thereby inhibiting HSC activation and attenuating fibrosis progression.^17,18 These findings not only provide novel insights into the mechanisms of ER stress but also underscore the therapeutic potential of natural compounds in combating liver fibrosis. However, challenges such as poor bioavailability and limited targeting hinder their clinical application. Emerging nano-delivery systems, including liposomes and polymeric nanoparticles, offer promising solutions by enhancing stability, enabling targeted delivery to HSCs, and improving therapeutic efficacy.¹⁹ The integration of nanotechnology with natural compounds represents an advanced strategy for precise ER stress modulation in liver fibrosis treatment.

This review aims to comprehensively examine the role of ER stress in the pathogenesis of liver fibrosis and explore the therapeutic potential of natural compounds that target ER stress. First, we will elucidate the molecular mechanisms of ER stress and its contribution to liver fibrosis. Next, we will highlight key natural compounds that modulate ER stress and discuss their mechanisms of action. Finally, we will address the limitations of current research and outline future directions to advance this promising field. By providing a thorough overview, this review seeks to offer new perspectives on the treatment of liver fibrosis and to promote the development of natural compounds as viable therapeutic options.

ER Stress and UPR

The ER is a membranous organelle in eukaryotic cells, extending from the nuclear envelope and consisting of two distinct regions: the rough ER and the smooth ER. The ER is a multifunctional organelle responsible for the synthesis, processing, and transport of proteins and lipids, as well as the regulation of calcium homeostasis and cellular signaling. Under stress conditions such as nutrient deprivation or hypoxia, misfolded or unfolded proteins accumulate within the ER lumen. This accumulation disrupts protein homeostasis, triggering ER stress.²⁰ The UPR responds to ER stress by enhancing protein folding, degrading misfolded proteins via ER-associated protein degradation (ERAD), and reducing new protein synthesis, restoring ER homeostasis and alleviating misfolded protein accumulation.^21,22 The biological outcomes of ER stress activation vary depending on its severity: mild ER stress induces the UPR, lowering protein translation levels and reducing the generation of unfolded proteins, while severe ER stress triggers widespread UPR activation, including apoptotic pathways, ultimately leading to cell death.^20,23

The classical UPR signaling pathways are initiated by three ER transmembrane proteins: inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase R-like endoplasmic reticulum kinase (PERK). Among these, the 78 kDa glucose-regulated protein (GRP78), also known as immunoglobulin heavy chain-binding protein (BiP), is one of the most extensively studied ER chaperones.²⁴ Under non-stress conditions, GRP78 binds to the luminal domains of these three ER transmembrane sensors. The accumulation of unfolded or misfolded proteins in the ER lumen leads to the dissociation of GRP78 from these sensors, thereby activating the UPR.²⁵

IRE1 Pathway

IRE1 is the most evolutionarily conserved ER stress sensor and is a type I transmembrane protein found in the ER of all eukaryotes.²⁶ It contains a serine/threonine protein kinase domain and an RNase domain. When the kinase domain of IRE1α detects misfolded or unfolded proteins, it dissociates from GRP78, dimerizes, and undergoes autophosphorylation, activating its RNase domain.²⁷ The X-box binding protein 1 (XBP1) initially exists in an immature form but is spliced into its mature form (XBP1s) by the endonuclease activity of IRE1α under ER stress conditions. XBP1s then translocates to the nucleus, regulating the expression of genes involved in protein folding and ER-associated protein degradation (ERAD).²⁸ Subsequently, ERAD binds to the cytoplasmic ubiquitin proteasome system, reducing the accumulation of unfolded proteins and restoring ER homeostasis. Additionally, IRE1α activation can lead to mRNA degradation through a process known as regulated IRE1α-dependent decay (RIDD), further reducing the protein load.²⁹ Importantly, the IRE1α-XBP1s axis not only regulates genes involved in protein folding and ERAD but also directly orchestrates lipid biosynthesis. Under ER stress, XBP1s moves to the nucleus and activates transcriptional programs for fatty acid metabolism, triglyceride synthesis, and cholesterol biogenesis.^30,31 Specifically, the metabolic rewiring driven by lipid metabolism is a key driver of HSC activation, a central event in the pathogenesis of liver fibrosis.³²

ATF6

ATF6, a transmembrane protein that belongs to the leucine zipper transcription factor family, contains a cytoplasmic bZIP domain essential for transcription factor dimerization. It exists in two isoforms, ATF6α and ATF6β, whose activation is dependent on the dissociation of BiP and the exposure of their Golgi-targeting sequences.^33,34 When misfolded or unfolded proteins accumulate, ATF6α translocates to the Golgi apparatus, where it undergoes cleavage by site-1 protease (MBTPS1) and site-2 protease (MBTPS2), releasing a truncated form of ATF6f (ATF6p50) that exhibits activated transcription factor activity.³⁵ Subsequently, ATF6p50 migrates to the nucleus, where it binds to ER stress response elements I or II and induces the transcription and expression of genes such as GRP78, GRP94, C/EBP homologous protein (CHOP), and XBP1.³⁶

PERK

PERK is a transmembrane protein with an N-terminal stress-sensing domain and a cytoplasmic kinase domain. During ER stress, PERK dissociates from GRP78 and is activated through dimerization and autophosphorylation.³⁷ To alleviate ER stress, PERK phosphorylates the eukaryotic translation initiation factor 2α (eIF2α) at Ser-51, inhibiting the assembly of the 80S ribosome and preventing mRNA translation initiation, thereby reducing the load of newly synthesized proteins entering the ER lumen.³⁸ Additionally, eIF2α enhances the expression of the transcription factor activating transcription factor 4 (ATF4), which activates CHOP and regulates the expression of growth arrest and DNA damage-inducible protein 34 (GADD34).³⁹ This response promotes the dephosphorylation of eIF2α, restoring protein translation after ER damage. In this process, CHOP can also act as a pro-apoptotic factor by triggering caspase-8 through death receptor 5 (DR5).⁴⁰ Figure 1.

Figure 1 The unfolded protein response pathway. (A) IRE1 Pathway: BiP dissociation triggers IRE1 dimerization and RNase activation. IRE1 splices XBP1u mRNA to produce the active transcription factor XBP1s, which drives expression of ER cghaperones, ERAD and lipid metabolism genes. (B) ATF6 Pathway: Released ATF6 translocates to the Golgi for proteolytic cleavage. The cytosolic fragment (ATF6p50) moves to the nucleus to upregulate chaperones like GRP78 and XBP1. (C) PERK Pathway: Active PERK phosphorylates eIF2α, attenuating global protein synthesis while selectively translating ATF4. ATF4 induces genes for stress response and, under prolonged stress, the pro-apoptotic factor CHOP.

ER Stress and Liver Fibrosis

The homeostasis of the liver is maintained through the synergistic action of diverse cell populations, primarily categorized into parenchymal and non-parenchymal cells. Approximately 65% of liver cells are parenchymal cells, primarily hepatocytes with a minor population of cholangiocytes, which are essential for liver regeneration following injury. Non-parenchymal cells, on the other hand, include HSCs, liver sinusoidal endothelial cells, and various immune components such as macrophages, natural killer cells, and dendritic cells, which collectively contribute to immune surveillance, inflammation regulation, and tissue repair.^41–43

ER Stress in Parenchymal Cells

In parenchymal cells, particularly hepatocytes, ER stress serves as a critical molecular mechanism linking various hepatic injuries to fibrogenesis. Hepatocytes, being the primary metabolic units of the liver, are exceptionally vulnerable to ER stress due to their high protein synthesis burden and involvement in detoxification processes. Multiple pathogenic pathways converge on ER stress in these cells. For instance, QRICH1 enhances HBV-induced hepatic fibrosis by promoting ER stress-mediated high-mobility group box 1 (HMGB1) translocation and secretion, establishing a pro-fibrotic microenvironment.⁴⁴ Similarly, GP73 upregulation during HBV infection mediates transforming growth factor β 1 (TGF-β1)-induced fibrogenic effects through the Smad2-ER stress axis in hepatocyte models.⁴⁵

In metabolic contexts, CYP2E1 promotes liver fibrosis by inducing oxidative stress and ER stress in response to high-cholesterol diets, creating a vicious cycle of hepatocyte damage and inflammation.⁴⁶ The loss of protective mechanisms also contributes significantly; PCSK9 deficiency exacerbates hepatic steatosis and fibrosis through CD36-mediated lipid accumulation, leading to ER stress and inflammatory activation.⁴⁷ Conversely, several protective factors mitigate these processes. Fibroblast growth factor 21 (FGF21) demonstrates remarkable hepatoprotective effects by attenuating steatosis, lipotoxicity, and ER stress, thereby reducing the activation of downstream fibrogenic pathways.⁴⁸ GDF15 similarly suppresses fibrosis-related genes and alleviates NASH phenotypes through modulation of ER stress responses.⁴⁹

The transcription factor CHOP, a key mediator of ER stress-induced apoptosis, is upregulated in various fibrotic models and promotes fibrosis not only through hepatocyte death but also by facilitating alternative activation of pro-fibrotic macrophages in schistosomiasis models.⁵⁰ Additionally, TRC8 deficiency exacerbates NASH progression by enhancing ER stress and apoptosis, while its overexpression ameliorates these effects, highlighting its crucial role in maintaining ER protein homeostasis in hepatocytes.⁵¹ These findings collectively demonstrate that ER stress in parenchymal cells acts as both a sensor of hepatic injury and an active contributor to the fibrotic cascade through multiple interconnected mechanisms.

ER Stress in Non-Parenchymal Cells

The role of ER stress in non-parenchymal cells, particularly HSCs and immune cells, represents a crucial mechanism in fibrosis progression. In HSCs, ER stress is not merely a consequence of activation but actively drives their transition to pro-fibrotic myofibroblasts. The thiol-disulfide oxidoreductase TXNDC5 is significantly upregulated in activated HSCs, where it promotes cell viability and collagen production through ER stress modulation, making it a promising therapeutic target.⁵² Similarly, Derlin-1 accelerates NASH progression by enhancing ERAD activity and ER stress, leading to RIPK3-mediated necroptosis in HSCs.⁵³

The collagen secretion machinery in HSCs is intimately connected to ER homeostasis. TANGO1, an ER-resident protein essential for collagen transport, is upregulated during HSC activation in an XBP1-dependent manner. Its depletion causes procollagen I retention, inducing severe UPR activation and ultimately HSC apoptosis.⁵⁴ Ion channels play a pivotal role in modulating ER stress and its downstream effects in HSCs, thereby influencing liver fibrosis. For instance, the acid-sensing ion channel 1a (ASIC1a) promotes HSC activation primarily by facilitating proton and calcium influx. This disruption of ionic homeostasis, particularly calcium overload within the ER lumen, impairs chaperone function and protein folding, thereby activating the UPR. The ensuing ER stress then drives fibrogenesis through the PI3K/AKT pathway.^55,56 The UPR branches play distinct roles, with IRE1α signaling typically promoting fibrogenesis, while AT2R attenuates fibrosis by suppressing the IRE1α-XBP1 pathway in HSCs.⁵⁷

In immune cells, particularly macrophages, ER stress significantly influences fibrotic progression. IRE1α activation in macrophages promotes pyroptosis and accelerates MASH progression through the IRE1α-GSDMD pathway, with its inhibition showing protective effects.⁵⁸ CHOP promotes liver fibrosis in schistosomiasis by facilitating alternative macrophage activation and M2 polarization.⁵⁰ Additionally, adipocyte-derived factors contribute to this network; PCPE1 functions as a BAT-derived profibrotic adipokine that promotes liver fibrosis through ER stress-induced secretion.⁵⁹

The interplay between different non-parenchymal cells further complicates the ER stress-fibrosis axis. HMGB1 released from injured hepatocytes activates HSCs via toll-like receptor 4(TLR4)/RAGE-mediated ER stress, creating a paracrine loop that sustains fibrogenesis.⁶⁰ Meanwhile, protective mechanisms also exist; Atp6v0d2 maintains hepatic lipid homeostasis and suppresses MASH progression by inhibiting XBP1-regulated ER stress in macrophages.⁶¹ These findings highlight the complex, cell-type-specific roles of ER stress in non-parenchymal cells and emphasize the potential of targeted therapies that modulate specific ER stress pathways in different cell populations to combat liver fibrosis.

In summary, ER stress serves as a pivotal pathogenic link that connects diverse hepatic injuries to the progression of liver fibrosis. It orchestrates fibrogenesis through cell-type-specific mechanisms: in parenchymal cells, such as hepatocytes, ER stress promotes apoptosis, inflammatory signaling, and the release of pro-fibrotic factors. Concurrently, in non-parenchymal cells, it directly activates HSCs and modulates immune responses, including macrophage polarization. The intricate cross-talk between these cell populations, particularly between injured hepatocytes and HSCs, as shown in Figure 2. This multifaceted involvement highlights the therapeutic potential of targeting cell-specific ER stress pathways as a promising strategy to mitigate liver fibrosis. Table 1.

Table 1 Genetic Regulators of Liver Fibrosis via ER Stress Pathways

Figure 2 Cross-talk between hepatocytes and stellate cells in the formation of fibrosis. Injured hepatocytes release HMGB1, TGF-β1, and ROS, activating HSCs into myofibroblasts. Activated HSCs secrete collagen, cytokines (eg, IL-6, TNF-α), and ROS, exacerbating hepatocyte damage and ER stress. Key pathways include TLR4/RAGE signaling, UPR activation, and oxidative stress. ER stress in hepatocytes promotes apoptosis and inflammatory signaling, while in HSCs, it drives collagen production and myofibroblast transition. The paracrine loop sustains fibrosis through HMGB1, TGF-β1, and ROS. Therapeutic targets include TXNDC5, IRE1α, and ASIC1a to disrupt this pathological interaction, highlighting the complex interplay between hepatocytes and HSCs in liver fibrosis progression.

ER Stress-Targeting Natural Compound

ER stress is increasingly recognized as a central mechanism driving hepatic fibrogenesis, drawing significant interest as a therapeutic target. A wide array of natural compounds demonstrates potent anti-fibrotic efficacy by modulating ER stress pathways. These substances can be functionally grouped into two strategic categories: one that suppresses detrimental ER stress to preserve hepatocyte function and inhibit HSCs activation, and another that selectively induces pro-apoptotic ER stress in activated HSCs, promoting their elimination.

Compounds That Ameliorate ER Stress

Numerous natural compounds alleviate liver fibrosis primarily by inhibiting maladaptive unfolded protein response (UPR) signaling, which in turn reduces hepatocyte apoptosis, inflammation, and HSC activation. Among these, polyphenols and flavonoids constitute a prominently effective class. For example, resveratrol downregulates pivotal ER stress markers such as CHOP, Bip, and caspases-3/7/12, while concurrently inhibiting pro-inflammatory pathways like TGF-β and NF-κB in carbon tetrachloride (CCl₄)-induced rodent models and in vitro HSC cultures.⁸⁵ Similarly, didymin exerts a broad inhibitory effect across all three UPR sensors, such as ATF6, IRE1α, and PERK, thereby mitigating apoptotic signaling and abnormal glycerophospholipid metabolism.⁸⁶ Additional flavonoids, including naringenin and tetrahydropalmatine, suppress critical UPR axes such as PERK-eIF2α-ATF4-CHOP and IRE1α-XBP1, significantly attenuating fibrotic progression.^87,88

Beyond polyphenols, several alkaloids and organic acids also play crucial roles. Berberine specifically targets the ATF6/SREBP-1c pathway, reducing lipid synthesis and ER stress, which leads to improved hepatic steatosis and fibrosis in metabolic models.⁸⁹ Likewise, p-coumaric acid and oxymatrine alleviate oxidative and ER stress, with oxymatrine notably enhancing calcium homeostasis in HSCs through regulation of Sarco/endoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2).^90,91 Among terpenoids and other structurally distinct compounds, additional mechanisms emerge. Irisin modulates PERK phosphorylation to stabilize the RNA-binding protein HNRNPA1, thereby conferring protection against fibrotic signaling.⁹² Meanwhile, lycopene inhibits the apoptosis signal-regulating kinase 1 (ASK1)-JNK pathway, and tanshinone IIA activates the PPARα/FGF21 axis, both resulting in suppression of ER stress and fibrosis in non-alcoholic steatohepatitis (NASH) models.^93,94 Furthermore, salvianolic acid A activates SIRT1, leading to HSF1 deacetylation and subsequent downregulation of the UPR, offering another layer of protection against HSC activation.⁹⁵

Compounds That Induce Pro-Apoptotic ER Stress in Activated HSCs

In contrast, a complementary anti-fibrotic strategy employs natural compounds to selectively induce lethal levels of ER stress in activated HSCs, triggering their apoptosis and facilitating the clearance of these key fibrogenic cells. Quinones and terpenoids are notably effective in this regard. Cryptotanshinone promotes activated HSC apoptosis by upregulating ER stress markers including CHOP and GRP78 and activating UPR-related molecules such as PERK, IRE1α, and ATF4.⁹⁶ Curcumol, a sesquiterpenoid, uniquely provokes necroptosis in activated HSCs via RIP3, a process modulated through Sirt1/Notch signaling under ER stress conditions.⁹⁷

Flavonoids also contribute significantly to this targeted approach. Quercetin and oroxylin A effectively initiate ER stress pathway activation, resulting in increased CHOP expression, altered Bcl-2-associated X protein (Bax)/ B-cell lymphoma 2 (Bcl-2) ratios, and caspase activation, collectively driving activated HSC apoptosis.^96,98 Similarly, malvidin induces programmed cell death through both ER stress and mitochondrial pathways.⁹⁹ Even some synthetic agents, such as etoposide, operate through this mechanism, inducing ER stress and JNK-mediated apoptosis in human HSC line LX-2.¹⁰⁰

Novel Mechanisms and Emerging Compounds

Recent research continues to uncover natural compounds with innovative anti-fibrotic mechanisms centered on ER stress modulation. For instance, 12-deoxyphorbol 13-palmitate represents a novel strategy by specifically targeting the protein Apolipoprotein L2 (APOL2), disrupting its interaction with SERCA2, and thereby inhibiting the pro-fibrotic PERK–HES1 signaling cascade.¹⁰¹ Another compound, senkyunolide A, exhibits specificity for cholestatic fibrosis models. It binds to CLCC1 and promotes its ubiquitination, which inhibits ER calcium release and suppresses ER autophagy, ultimately reducing cholangiocyte proliferation and ductular reaction.¹⁰² Additionally, arctigenin mitigates HSC activation through dual mechanisms: not only does it suppress ER stress, but it also restores lipid homeostasis via modulation of the ERAD pathway, underscoring the interplay between proteostasis and metabolic regulation in liver fibrosis.¹⁰³ Table 2

Table 2 Natural Compounds Targeting ER Stress for Liver Fibrosis

Current Research and Future Perspective

The compelling preclinical evidence supporting ER stress as a therapeutic target in liver fibrosis has not yet translated into effective clinical treatments. A primary obstacle lies in the suboptimal pharmacokinetic profiles of many promising natural compounds, including poor aqueous solubility, metabolic instability, and, crucially, non-specific biodistribution, which collectively result in low bioavailability and limited efficacy at the target site.¹¹⁸ Therefore, the development of advanced delivery strategies that can enhance the stability of these compounds and direct them precisely to specific liver cell populations is paramount for clinical translation.

Nanoparticle-based delivery systems have emerged as a transformative strategy to overcome these pharmacological hurdles.^119,120 The core advantage of these systems is their ability to be engineered for cell-specific targeting within the complex liver microenvironment. For instance, targeting hepatocytes can be achieved by functionalizing nanocarriers with galactose or lactose ligands, which are recognized by the asialoglycoprotein receptor highly expressed on hepatocytes.¹²¹ This approach allows for the precise delivery of therapeutic agents to alleviate ER stress induced by metabolic insults or viral infections within parenchymal cells. However, the success of anti-fibrotic therapy hinges even more critically on targeting non-parenchymal cells. A well-established strategy exploits the vitamin A storage characteristic of HSCs by using retinol-coupled liposomes or polymeric nanoparticles, which enables the selective delivery of pro-apoptotic or anti-fibrotic agents directly to activated HSCs. Vitamin A-coupled nanoparticles, such as retinol-modified crosslinking nanopolyplexes, hijack retinol-binding protein for precise activated HSC targeting and ROS-responsive siRNA release, effectively reducing collagen deposition and liver injury in preclinical models.¹²² Furthermore, other targeting ligands, such as those binding to the platelet-derived growth factor receptor β or integrins upregulated on activated HSCs, are under active investigation to achieve high specificity.^123,124

Beyond conventional active targeting, the frontier of drug delivery involves biomimetic nanocarriers.^125,126 These innovative systems, such as those camouflaged with membranes derived from platelets or even activated HSCs themselves, inherit the complex surface proteins and “self” markers of the source cells. This biomimicry offers unparalleled targeting precision to the fibrotic niche and enhances immune evasion, representing a significant breakthrough for site-specific drug release. Moreover, the development of “smart” nanocarriers, such as the CXCR4-targeted ROS-responsive platform AMD-Dex-ROS-sorafenib, leverages high intracellular ROS levels in activated HSCs for thioketal rupture and on-demand drug release.¹²⁷

Notwithstanding the promise of advanced delivery systems, several formidable challenges remain. Firstly, the vast majority of evidence is derived from rodent models, creating a critical gap in clinical validation. There is an urgent and unmet need for well-designed Phase I and II clinical trials that rigorously evaluate the safety and efficacy of the most promising candidates, such as curcumin or berberine, in patients with chronic liver diseases.¹²⁸ Another significant challenge lies in the dualistic nature of the UPR. While inhibiting chronic, maladaptive ER stress is beneficial, uncontrolled suppression can disrupt the UPR’s essential adaptive functions in protein homeostasis.

To successfully bridge the translational gap, future research should prioritize several key directions. Advanced human-relevant preclinical models, including patient-derived organoids and 3D-bioprinted liver tissues, will be crucial for better predicting drug efficacy and toxicity before costly clinical trials.^129,130 Concurrently, multi-omics technologies such as genomics and proteomics, along with high-throughput screening, will accelerate the discovery of novel natural compounds and precisely define their molecular targets within the complex UPR network.¹³¹ Finally, exploring rational combination therapies that synergize ER stress-targeting natural compounds delivered via sophisticated nanocarriers with existing anti-fibrotic agents or first-line treatments like antivirals represents a highly promising strategic direction. In summary, by addressing these challenges through interdisciplinary collaboration integrating pharmacology, nanotechnology, and clinical science, the field can move closer to harnessing the full potential of ER stress modulation as a viable and precise therapeutic strategy for patients with liver fibrosis.

Conclusion

This review establishes the unequivocal role of ER stress as a central mechanism in the pathogenesis of liver fibrosis, orchestrating a complex interplay of cellular responses in both hepatocytes and HSCs. The extensive catalogue of natural compounds presented herein not only validates ER stress as a druggable target but also offers a rich reservoir of potential therapeutic agents capable of modulating the UPR to halt or reverse fibrogenesis. However, the inherent limitations of these compounds, particularly their pharmacokinetic drawbacks, underscore a critical translational challenge. The advent of sophisticated biomimetic nanotechnologies, exemplified by cell membrane-camouflaged platforms, provides a transformative solution to these obstacles, enabling targeted delivery and maximizing on-site therapeutic efficacy while minimizing off-target effects. Looking forward, the future of anti-fibrotic therapy lies in the convergence of pharmacology, nanotechnology, and precision medicine. Prioritizing the development of intelligent nano-formulations for lead natural compounds, validating their efficacy in human-relevant models, and exploring synergistic combination therapies will be paramount. By harnessing these innovative strategies, the field can successfully translate the compelling preclinical promise of ER stress modulation into tangible clinical benefits for patients suffering from liver fibrosis.

Abbreviations

APOL2, Apolipoprotein L2; ASK1, Apoptosis Signal-regulating Kinase 1; ATF4, Activating Transcription Factor 4; ATF6, Activating Transcription Factor 6; Bax, Bcl-2-Associated X Protein; Bcl-2, B-Cell Lymphoma 2; BiP, Immunoglobulin Heavy Chain-Binding Protein; CHOP, C/EBP Homologous Protein; ECM, Extracellular Matrix; eIF2α, Eukaryotic Initiation Factor 2 Alpha; ER, Endoplasmic Reticulum; ERAD, Endoplasmic Reticulum-Associated Protein Degradation; ER stress, Endoplasmic Reticulum Stress; FGF21, Fibroblast Growth Factor 21; GADD34, Growth Arrest and DNA Damage-inducible protein 34; GSDMD, Gasdermin D; GRP78, 78-kDa Glucose-Regulated Protein; HSCs, Hepatic Stellate Cells; HMGB1, High-Mobility Group Box 1; PERK, Protein Kinase R-like Endoplasmic Reticulum Kinase; RIDD, Regulated IRE1α-Dependent Decay; SERCA2, Sarco/Endoplasmic Reticulum Ca²⁺-ATPase 2; TGF-β1, Transforming Growth Factor Beta 1; TLR4, Toll-Like Receptor 4; UPR, Unfolded Protein Response; XBP1, X-Box Binding Protein 1.

Acknowledgments

Figure were created in https://www.figdraw.com and https://BioRender.com.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

Macau Science and Technology Development fund (FDCT (0012/2021/AMJ, 0001/2024/RDP, 0001/2024/AKP, 0092/2022/A2, 0144/2022/A3).

Disclosure

The authors declare no competing interest.

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