Matrisome gene-based subclassification of patients with liver fibrosis identifies clinical and molecular heterogeneities.

BACKGROUND AIMS: Excessive deposition and crosslinking of extracellular matrix increases liver density and stiffness, promotes fibrogenesis, and increases resistance to fibrinolysis. An emerging therapeutic opportunity in liver fibrosis is to target the composition of the extracellular matrix or block pathogenic communication with surrounding cells. However, the type and extent of extracellular changes triggering liver fibrosis depend on the underlying etiology. Our aim was to unveil matrisome genes not dependent on etiology, which are clinically relevant to liver fibrosis. APPROACH RESULTS: We used transcriptomic profiles from liver fibrosis cases of different etiologies to identify and validate liver fibrosis-specific matrisome genes (LFMGs) and their clinical and biological relevance. Dysregulation patterns and cellular landscapes of LFMGs were further explored in mouse models of liver fibrosis progression and regression by bulk and single-cell RNA sequencing. We identified 35 LFMGs, independent of etiology, representing an LFMG signature defining liver fibrosis. Expression of the LFMG signature depended on histological severity and was reduced in regressive livers. Patients with liver fibrosis, even with identical pathological scores, could be subclassified into LFMG Low and LFMG High , with distinguishable clinical, cellular, and molecular features. Single-cell RNA sequencing revealed that microfibrillar-associated protein 4 + activated HSC increased in LFMG High patients and were primarily responsible for the LFMG signature expression and dysregulation. CONCLUSIONS: The microfibrillar-associated protein 4 + -activated HSC-derived LFMG signature classifies patients with liver fibrosis with distinct clinical and biological characteristics. Our findings unveil hidden information from liver biopsies undetectable using traditional histologic assessments.

Selective Inhibition of Hepatic Stellate Cell and Fibroblast-derived LOXL1 Attenuates BDL and Mdr2-/- Induced Cholestatic Liver Fibrosis.

BACKGROUND AND AIMS: Lysyl oxidase-like 1 (LOXL1) proteins are amine oxidases that play a crucial role in extracellular matrix remodeling due to their collagen cross-linking and intracellular functions. The role of LOXL1 in cholestatic liver fibrosis remains unexplored. METHODS: We measured LOXL1 expression in two murine models of cholestasis (Mdr2 knockout [Mdr2-/-] and bile duct ligation [BDL]). We used adeno-associated virus (AAV) serotype 6-mediated hepatic delivery against LOXL1 (AAV2/6-shLoxl1) to investigate the therapeutic efficacy of targeting LOXL1 in cholestatic liver fibrosis. NIH-3T3 murine fibroblasts were used to investigate the function and regulatory mechanisms of LOXL1 in vitro. RESULTS: LOXL1 expression was significantly upregulated in Mdr2 -/- and BDL mice compared to their corresponding controls, predominantly in collagen-rich fibrous septa and portal areas. AAV2/6-shLoxl1 significantly reduced LOXL1 levels in Mdr2-/- and BDL mice, mainly located in desmin-positive hepatic stellate cells (HSCs) and fibroblasts. Concomitant with reduced LOXL1 expression, there was reduced ductular reaction, inflammation, and fibrosis in both Mdr2 -/- and BLD mouse models. Additionally, Loxl1 intervention decreased Ki-67 positive cells in the desmin-positive areas in both Mdr2 -/- and BDL mice. Overexpression of LOXL1 significantly promoted fibroblast proliferation by activating the platelet-derived growth factor receptor and extracellular signal-regulated kinase signaling pathways in vitro. CONCLUSION: Our findings demonstrated that selective inhibition of LOXL1 derived from HSCs/fibroblasts attenuated cholestatic liver/biliary fibrosis, inflammation, ductal reaction, and HSC/fibroblast proliferation. Based on our findings LOXL1 could be a potential therapeutic target for cholestatic fibrosis.

Aryl hydrocarbon receptor attenuates cholestatic liver injury by regulating bile acid metabolism.

Cholestatic liver disease is defined as the bile acids (BAs) accumulation in the liver caused by impaired synthesis, and secretion, together with excretion of BAs due to a variety of factors, which, if left untreated, can result in hepatic fibrosis, cholestatic cholangitis, cholestatic cirrhosis, eventually, end-stage liver disease. Currently, modulation of BA metabolism is still a prospective therapeutic strategy for treating the cholestatic diseases. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with far-reaching effects on the chronic liver disease. However, its role and mechanism in cholestatic liver damage is still unknown. Therefore, in this work, we explored the impact of AHR on the cholestatic liver injury using AHR overexpression mediated by adeno-associated viral (AAV) vectors. We found that AHR is differentially expressed in different stages of cholestatic liver disease, showing either down-regulation or an increase in protective effects. Overexpression of AHR increased body weight, decreased serum total bilirubin (TBil) and alkaline phosphatase (ALP), reduced porphyrin accumulation in liver tissue, and regulated the bile acid pool in the cholestatic mouse model induced by DDC diet. Overall, our data indicate that AHR attenuated cholestatic liver injury. AHR function indicates that it may have an action in the clinical management of cholestasis.

Selective depletion of hepatic stellate cells-specific LOXL1 alleviates liver fibrosis.

The role of LOXL1 in fibrosis via mediating ECM crosslinking and stabilization is well established; however, the role of hepatic stellate cells (HSCs)-specific LOXL1 in the development of fibrosis remains unknown. We generated HSCs-specific Loxl1-depleted mice (Loxl1Gfap-cre mice) to investigate the HSCs-specific contribution of LOXL1 in the pathogenesis of fibrosis. Loxl1fl/fl mice were used as the control. Furthermore, we used RNA sequencing to explore the underlying changes in the transcriptome. Results of the sirius red staining, type I collagen immunolabeling, and hydroxyproline content analysis, coupled with the reduced expression of profibrogenic genes revealed that Loxl1Gfap-cre mice with CCl4 -induced fibrosis exhibited decreased hepatic fibrosis. In addition, Loxl1Gfap-cre mice exhibited reduced macrophage tissue infiltration by CD68-positive cells and decreased expression of inflammatory genes compared with the controls. RNA sequencing identified integrin α8 (ITGA8) as a key modulator of LOXL1-mediated liver fibrosis. Functional analyses showed that siRNA silencing of Itga8 in cultured fibroblasts led to a decline in the LOXL1 expression and inhibition of fibroblast activation. Mechanistic analyses indicated that LOXL1 activated the FAK/PI3K/AKT/HIF1a signaling pathway, and the addition of inhibitors of FAK or PI3K reversed these results via downregulation of LOXL1. Furthermore, HIF1a directly interacted with LOXL1 and upregulated its expression, indicating that LOXL1 can positively self-regulate by forming a positive feedback loop with the FAK/PI3K/AKT/HIF1a pathway. We demonstrated that HSCs-specific Loxl1 deficiency prevented fibrosis, inflammation and that ITGA8/FAK/PI3K/AKT/HIF1a was essential for the function and expression of LOXL1. Knowledge of this approach can provide novel mechanisms and targets to treat fibrosis in the future.

Dynamics of elastin in liver fibrosis: Accumulates late during progression and degrades slowly in regression.

Elastin is an amorphous protein highly resistant to elastase degradation and is believed to be the most stable component among the extracellular matrix (ECM) members. Thus the excessive deposition of elastin in advanced liver fibrosis may contribute to the declining reversibility of the disease. Our previous study has found that elastin crosslinking inhibition can effectively arrest liver fibrosis progression. To further understand the roles of elastin involved in liver fibrosis, we systematically investigated the expression, accumulation, and degradation based on dynamic and bidirectional CCl4 -induced liver fibrosis mouse models and visualized the ultrastructure of elastin globules in cultured LX-2 cells. We found that the expression pattern of tropoelastin (soluble elastin) and collagen I was not completely comparable at both the transcriptional and posttranscriptional levels during liver fibrosis progression and regression. Elastin mainly accumulated onto the internodular fibrous septa and enlarged portal areas and intertwined with collagen I at the late stage of liver fibrosis. Three-dimensional analysis of elastin and collagen I by confocal immunofluorescence coupled with biochemical analyses revealed that with respect to collagen, elastin deposition was characterized by late aggregation in progression and slow turnover in regression. In addition, we visualized the dynamic ultrastructure of ECM fibers during liver fibrogenesis and fibrolysis and the ultrastructure of elastin globules self-aggregated by tropoelastin crosslinking. Our current study established new general hallmarks of elastin levels and forms in progressive and regressive liver fibrosis and provided a foundation for further experimental investigation of the growing role of elastin in liver fibrosis regression.

Multitranscriptome analyses reveal prioritized genes specifically associated with liver fibrosis progression independent of etiology.

Elimination or suppression of causative factors can raise the possibility of liver fibrosis regression. However, different injurious stimuli will give fibrosis from somewhat different etiologies, which, in turn, may hamper the discovery of liver fibrosis-specific therapeutic drugs. Therefore, the analogical cellular and molecular events shared by various etiology-evoked liver fibrosis should be clarified. Our present study systematically integrated five publicly available transcriptomic data sets regarding liver fibrosis with different etiologies from the Gene Expression Omnibus database and performed a series of bioinformatics analyses and experimental verifications. A total of 111 significantly upregulated and 16 downregulated genes were identified specific to liver fibrosis independent of any etiology. These genes were predominately enriched in some Kyoto Encyclopedia of Genes and Genomes pathways, including the "PI3K-AKT signaling pathway," "Focal adhesion," and "ECM-receptor interaction." Subsequently, five prioritized liver fibrosis-specific genes, including COL4A2, THBS2, ITGAV, LAMB1, and PDGFRA, were screened. These genes were positively associated with each other and liver fibrosis progression. In addition, they could robustly separate all stages of samples in both training and validation data sets with diverse etiologies when they were regarded as observed variables applied to principal component analysis plots. Expressions of all five genes were confirmed in activated primary mouse hepatic stellate cells (HSCs) and transforming growth factor ß1-treated LX-2 cells. Moreover, THBS2 protein was enhanced in liver fibrosis rodent models, which could promote HSC activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs. Overall, our current study may provide potential targets for liver fibrosis therapy and aid to a deeper understanding of the molecular underpinnings of liver fibrosis. NEW & NOTEWORTHY Prioritized liver fibrosis-specific genes THBS2, COL4A2, ITGAV, LAMB1, and PDGFRA were identified and significantly associated with liver fibrosis progression and could be combined to discriminate liver fibrosis stages regardless of any etiology. Among the identified prioritized liver fibrosis-specific targets, THBS2 protein was confirmed to be enhanced in liver fibrosis rodent models, which could promote hepatic stellate cell (HSC) activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs.

Inhibition of lysyl oxidase-like 1 (LOXL1) expression arrests liver fibrosis progression in cirrhosis by reducing elastin crosslinking.

Mature crosslinked-poly-elastin deposition has been found to be associated with liver fibrosis. However, the regulation of crosslinked/insoluble elastin in liver fibrosis remains largely unknown. Here, we investigated the contribution of lysyl oxidases (LOXs) family, mediated elastin crosslinking, to liver fibrogenesis. We established carbon tetrachloride (CCl4)-induced liver fibrotic and cirrhotic models and found that crosslinked/insoluble elastin levels spiked only in cirrhosis stage during disease progression, in comparison to collagen Ι levels which increased continuously though all stages. Among the LOXs family members, only LOX-like 1 (LOXL1) levels were coincident with the appearance of crosslinked/insoluble elastin. These coincidences included that LOXL1 expression increased (34 fold) in cirrhosis, localized with α-smooth muscle actin (SMA) and was absent in normal and fibrotic livers. In LX-2 cells, LOXL1 silencing arrested expression of α-SMA, elastin and collagen Ι. Our previously characterized adeno-associated vector (AAV) 2/8 shRNA was shown to effectively downregulate LOXL1 expression in CCl4 induced fibrosis mice models. These resulted in delicate and thinner septa and less crosslinked elastin, with a 58% loss of elastin area and 51% decrease of collagen area. Our findings strongly suggested that elastin crosslinking and LOXL1 were co-associated with liver cirrhosis, while selective inhibition of LOXL1 arrested disease progression by reducing crosslinking of elastin.

Mitochondria-Associated Membranes in Aging and Senescence.

Although the pursuit of eternal youth remains elusive, progress in the fields of medicine and science has greatly extended the human lifespan. Nevertheless, the rising incidence of diseases and their economic impact present notable obstacles. Mitochondria-associated membranes (MAMs), essential sites for close interaction between mitochondria and the endoplasmic reticulum (ER), are increasingly recognized for their involvement in both normal cellular processes and the development of diseases. Studies suggest that MAMs undergo dynamic alterations, particularly pertinent in the investigation of age-related illnesses. This review highlights the significance of MAMs in age-related conditions, elucidating the morphological and functional alterations in mitochondria and ER during aging. By emphasizing the complex interaction between these organelles, it demonstrates the cell's adaptive responses to combat age-related deterioration. Suggesting MAMs as potential targets for therapeutic interventions holds the potential for attenuating the progression of age-related diseases.

Crosstalk of lysyl oxidase-like 1 and lysyl oxidase prolongs their half-lives and regulates liver fibrosis through Notch signal.

BACKGROUND: Lysyl oxidase (LOX) family members (LOX and LOXL1 to 4) are crucial copper-dependent enzymes responsible for cross-linking collagen and elastin. Previous studies have revealed that LOX and LOXL1 are the most dramatically dysregulated LOX isoforms during liver fibrosis. However, the crosstalk between them and the underlying mechanisms involved in the profibrotic behaviors of HSCs, as well as the progression of liver fibrosis, remain unclear. METHODS: pCol9GFP-HS4,5Tg mice, Loxl1fl/flGfapCre mice, human HSC line, and primary HSCs were enrolled to study the dysregulation pattern, profibrotic roles, and the potential mechanisms of LOX and LOXL1 interaction involved in the myofibroblast-like transition of HSCs and liver fibrogenesis. RESULTS: LOX and LOXL1 were synergistically upregulated during liver fibrogenesis, irrespective of etiology, together orchestrating the profibrotic behaviors of HSCs. LOX and LOXL1 coregulated in HSCs, whereas LOXL1 dominated in the coregulation loop. Interestingly, the interaction between LOXL1 and LOX prolonged their half-lives, specifically enhancing the Notch signal-mediated myofibroblast-like transition of HSCs. Selective disruption of Loxl1 in Gfap+ HSCs deactivated the Notch signal, inhibited HSC activation, and relieved carbon tetrachloride-induced liver fibrosis. CONCLUSIONS: Our current study confirmed the synergistic roles and the underlying mechanisms of LOXL1 and LOX crosstalk in the profibrotic behaviors of HSCs and liver fibrosis progression, providing experimental evidence for further clear mechanism-based anti-LOXL1 strategy development in the therapy of liver fibrosis.

Targeting thrombospondin-2 retards liver fibrosis by inhibiting TLR4-FAK/TGF-ß signaling.

Background & Aims: Thrombospondin-2 (THBS2) expression is associated with liver fibrosis regardless of etiology. However, the role of THBS2 in the pathogenesis of liver fibrosis has yet to be elucidated. Methods: The in vivo effects of silencing Thbs2 in hepatic stellate cells (HSCs) were examined using an adeno-associated virus vector (serotype 6, AAV6) containing short-hairpin RNAs targeting Thbs2, under the regulatory control of cytomegalovirus, U6 or the α-smooth muscle promoter, in mouse models of carbon tetrachloride or methionine-choline deficient (MCD) diet-induced liver fibrosis. Crosstalk between THBS2 and toll-like receptor 4 (TLR4), as well as the cascaded signaling, was systematically investigated using mouse models, primary HSCs, and human HSC cell lines. Results: THBS2 was predominantly expressed in activated HSCs and dynamically increased with liver fibrosis progression and decreased with regression. Selective interference of Thbs2 in HSCs retarded intrahepatic inflammatory infiltration, steatosis accumulation, and fibrosis progression following carbon tetrachloride challenge or in a dietary model of metabolic dysfunction-associated steatohepatitis. Mechanically, extracellular THBS2, as a dimer, specifically recognized and directly bound to TLR4, activating HSCs by stimulating downstream profibrotic focal adhesion kinase (FAK)/transforming growth factor beta (TGF-ß) pathways. Disruption of the THBS2-TLR4-FAK/TGF-ß signaling axis notably alleviated HSC activation and liver fibrosis aggravation. Conclusions: THBS2 plays a crucial role in HSC activation and liver fibrosis progression through TLR4-FAK/TGF-ß signaling in an autocrine manner, representing an attractive potential therapeutic target for liver fibrosis. Impact and implications: Thrombospondin-2 (THBS2) is emerging as a factor closely associated with liver fibrosis regardless of etiology. However, the mechanisms by which THBS2 is involved in liver fibrosis remain unclear. Here, we showed that THBS2 plays a prominent role in the pathogenesis of liver fibrosis by activating the TLR4-TGF-ß/FAK signaling axis and hepatic stellate cells in an autocrine manner, providing a potential therapeutic target for the treatment of liver fibrosis.

CryoFIB milling large tissue samples for cryo-electron tomography.

Cryo-electron tomography (cryoET) is a powerful tool for exploring the molecular structure of large organisms. However, technical challenges still limit cryoET applications on large samples. In particular, localization and cutting out objects of interest from a large tissue sample are still difficult steps. In this study, we report a sample thinning strategy and workflow for tissue samples based on cryo-focused ion beam (cryoFIB) milling. This workflow provides a full solution for isolating objects of interest by starting from a millimeter-sized tissue sample and ending with hundred-nanometer-thin lamellae. The workflow involves sample fixation, pre-sectioning, a two-step milling strategy, and localization of the object of interest using cellular secondary electron imaging (CSEI). The milling strategy consists of two steps, a coarse milling step to improve the milling efficiency, followed by a fine milling step. The two-step milling creates a furrow-ridge structure with an additional conductive Pt layer to reduce the beam-induced charging issue. CSEI is highlighted in the workflow, which provides on-the-fly localization during cryoFIB milling. Tests of the complete workflow were conducted to demonstrate the high efficiency and high feasibility of the proposed method.

Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis.

BACKGROUND & AIMS: Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. METHODS: FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. RESULTS: FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. CONCLUSIONS: Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis.

Background and Aims: Iron overload can contribute to the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Hepcidin (Hamp), which is primarily synthesized in hepatocytes, is a key regulator of iron metabolism. However, the role of Hamp in NASH remains unclear. Therefore, we aimed to elucidate the role of Hamp in the pathophysiology of NASH. Methods: Male mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for 16 weeks to establish the mouse NASH model. A choline-supplemented amino acid-defined (CSAA) diet was used as the control diet. Recombinant adeno-associated virus genome 2 serotype 8 vector expressing Hamp (rAAV2/8-Hamp) or its negative control (rAAV2/8-NC) was administered intravenously at week 8 of either the CDAA or CSAA diet. Results: rAAV2/8-Hamp treatment markedly decreased liver weight and improved hepatic steatosis in the CDAA-fed mice, accompanied by changes in lipogenesis-related genes and adiponectin expression. Compared with the control group, rAAV2/8-Hamp therapy attenuated liver damage, with mice exhibiting reduced histological NAFLD inflammation and fibrosis, as well as lower levels of liver enzymes. Moreover, α-smooth muscle actin-positive activated hepatic stellate cells (HSCs) and CD68-postive macrophages increased in number in the CDAA-fed mice, which was reversed by rAAV2/8-Hamp treatment. Consistent with the in vivo findings, overexpression of Hamp increased adiponectin expression in hepatocytes and Hamp treatment inhibited HSC activation. Conclusions: Overexpression of Hamp using rAAV2/8-Hamp robustly attenuated liver steatohepatitis, inflammation, and fibrosis in an animal model of NASH, suggesting a potential therapeutic role for Hamp.

Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice.

BACKGROUND AND AIMS: Lysyl oxidase-like-1 (LOXL1), a vital cross-linking enzyme in extracellular matrix (ECM) maintenance, promotes fibrosis via enhancement of ECM stability. However, the potential role of LOXL1 in the pathogenesis of nonalcoholic steatohepatitis (NASH) has not been previously studied. METHODS: We generated Loxl1fl/fl mice to selectively delete LOXL1 in hepatic stellate cells (HSCs) (Loxl1fl/flGfapcre; Loxl1fl/fl as littermate controls) and then examined liver pathology and metabolic profiles in Loxl1fl/flGfapcre fed with either a choline-deficient L-amino acid-defined (CDAA) diet or an isocaloric control diet for 16 weeks. Thereafter, the findings from the animal model were confirmed in 23 patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD). RESULTS: LOXL1 was significantly increased in CDAA induced non-obese NASH compared with the control diet, and LOXL1 deficient in HSCs ameliorated CDAA-induced inflammation and fibrosis, with reduced expression of pro-inflammation and pro-fibrogenic genes in the HSCs-specific LOXL1 knockout mice model. Interestingly, LOXL1 deficient in HSCs could attenuate hepatic steatosis and reverse the metabolic disorder by restoring adipose tissue function without altering the effect of hepatic lipogenesis gene expression in non-obese NASH model. More importantly, analyses of serum LOXL1 and leptin levels from NAFLD patients revealed that LOXL1 was positively correlated with histological fibrosis progression, whereas it was inversely correlated with leptin levels, especially in non-obese NAFLD patients. CONCLUSION: LOXL1 may contribute to fibrosis progression in non-obese NAFLD, and HSCs-specific knockout of LOXL1 attenuated liver steatosis, inflammation, fibrosis, , and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH.

miRNA-150-5p promotes hepatic stellate cell proliferation and sensitizes hepatocyte apoptosis during liver fibrosis.

Aim: To explore the role of miRNA-150-5p (miR-150-5p) in liver fibrosis. Materials & methods: miRNA expression profiles, CCl4-induced liver fibrosis progression and regression rodent models, quantitative real-time PCR, miR-150-5p mimics and inhibitors, cell proliferation and apoptosis detection, RNA sequencing and bioinformatics analysis were employed. Results: Liver tissue miR-150-5p expression was positively associated with liver fibrosis progression and regression; however, miR-150-5p exhibited a cell-specific expression pattern, namely, it was enhanced in hepatocytes but reduced in hepatic stellate cells (HSCs) during liver fibrosis; miR-150-5p overexpression promoted HSC apoptosis and sensitized hepatocyte apoptosis; miR-150-5p mimic had a larger influence on the transcriptomic stability of HSCs than that of hepatocytes; miR-150-5p mediated activation of interferon signaling pathways might be responsible for HSC apoptosis. Conclusion: miR-150-5p exhibited an opposite regulation and function pattern between HSCs and hepatocytes during liver fibrosis.