The antitumor efficacy of immune cell engagers that bind two targets on the same immune cell is limited by structural constraints, leading to incomplete coengagement and uncoordinated signaling. Here, we develop a trispecific macrophage engager (TrME) that both activates the prophagocytic receptor lipoprotein receptor-related protein 1 (LRP1) and blocks the antiphagocytic receptor signal regulatory protein alpha (SIRPα). This 'activate and block' AND logic gate, when coupled to a tumor-targeting moiety, enables coordinated signaling that enhances macrophage cytotoxicity against solid tumors. The TrME tandemly links monovalent LRP1 activator calreticulin, anti-SIRPα scFv and a tumor-associated antigen (TAA)-targeting arm through flexible linkers. Computational modeling and screening of tandem constructs revealed an optimal conformation for robust cis-targeting, allowing logic-gated control of ratiometric prophagocytic and antiphagocytic signaling. In situ generation of TrME by delivering mRNA encoding TAA-targeting TrME through an optimized lipid nanoparticle system activates macrophages and induces antitumor responses, significantly inhibiting tumor growth and prolonging survival in multiple solid tumor mouse models.

Regeneration of hyaline cartilage remains a major clinical challenge. Current first-line treatments for focal articular cartilage defects, typically induce fibrocartilage instead of hyaline cartilage, resulting in inferior mechanical and biological outcomes. Here we report a biomimetic strategy inspired by the biosilicification process of diatoms, for the de novo synthesis of biosilica nanocages exhibiting effective binding to the hyaline chondrogenic cytokine transforming growth factor β1 (TGF-β1). To enhance clinical applicability, an injectable biosilica nanocage-based hydrogel (Si-aGel hydrogel) was further engineered to conformally fill cartilage defects of diverse geometries while exhibiting excellent mechanical performance. Si-aGel hydrogel preserves long-term hyaline chondrogenic commitment of rat primary bone marrow-derived mesenchymal stem/stromal cells (BMSCs) in vitro. Moreover, when injected into the full-thickness cartilage defects, Si-aGel hydrogel effectively sustained stable TGF-β1-activated chondral differentiation of BMSCs and promoted complete hyaline cartilage repair with a type II collagen- and aggrecan-rich hyaline matrix deposition without any exogenous supplements. In contrast, those without intervention or treated with hydrogel lacking biosilica nanocages developed fibrocartilaginous and hypertrophic repair tissue, marked by a disorganized matrix with abundant type I and type X collagen. Together, our study suggested the biosilica nanocage-based therapy has the great potential for hyaline cartilage regeneration.

The tumor microenvironment (TME) is increasingly recognized as a complex ecosystem shaped by dynamic interactions among tumor cells, immune cells, and microbial components. While growing evidence has established the microbiota as a key regulator of antitumor immunity and immunotherapy response, the contribution of bacteriophages, the most abundant biological entities within microbial communities, has remained largely overlooked. Recent studies suggest that bacteriophages are not merely passive regulators of bacterial populations but can actively modulate host immune responses and influence tumor-associated immune landscapes. In this review, we summarize emerging evidence suggesting that bacteriophages may influence antitumor immunity through both direct and indirect mechanisms. Evidence from immune-cell and non-cancer experimental systems indicates that phage nucleic acids can engage TLR9-dependent sensing and, for selected phages, STING-associated inflammatory signaling; however, the relevance of these pathways within human tumors remains to be established. Indirectly, phages may alter microbial community structure and metabolic outputs, which could influence systemic immune tone and the composition of immune infiltrates within the TME. We further discuss accumulating data linking phageome features with tumor progression and responses to immune checkpoint blockade and other cancer therapies. However, much of the available evidence remains preclinical, indirect, or correlative, and causal roles for endogenous phages in human tumor immunity still require further validation. Distinct from the putative ecological and immunological roles of naturally occurring phages, engineered bacteriophages are being developed as therapeutic platforms for cancer immunotherapy, including tumor-antigen display, targeted delivery of immune agonists, cytokines or nucleic acids, and combination strategies with existing treatments. Finally, we address key methodological, mechanistic, and safety challenges that must be overcome to translate phage-based immunomodulation into clinical applications. Collectively, this review highlights the phageome as an emerging regulatory layer of tumor immunity and a promising, yet underexplored, target for therapeutic intervention.

Aging is a major contributor to the increasing incidence of acute kidney injury (AKI) and chronic kidney disease (CKD), however the molecular events explaining aging-related nephropathies remains elusive. Here, we found that the RAS signaling adapter protein Erbin (ErbB2-interacting protein) is abundantly expressed in renal tubular cells, but its levels are decreased in murine AKI models and human CKD patient samples. Tubule-specific deletion of Erbin rendered mice highly susceptible to acute kidney injury, and exacerbated renal fibrosis. In contrast, restoring Erbin protected against AKI and CKD. Moreover, tubular Erbin loss in the naturally-aged kidney aggravates aging-associated nephropathies. Transcriptome sequencing revealed a causal association between Erbin loss and cell-cycle alterations in tubular epithelial cells. Depleting Erbin increased the proportion of tubular cells in G2/M phase and accelerated cellular senescence in vitro and in vivo. Mechanistically, Erbin protects tubular cells from senescence by stabilizing YB-1, which maintains CDK1 and cyclin B1 expression, and facilitates cell-cycle progression. Thus, restoring Erbin represents a potential strategy for chronic kidney disease and aging nephropathies. The molecular events initiating aging-related nephropathies such as acute kidney injury (AKI) and chronic kidney disease (CKD) remain elusive. This study shows that loss of ErbB2-interacting protein (Erbin) triggers senescence in renal tubule cells by destabilizing YB-1 and impairing cell-cycle progression. ErbB2-interacting protein Erbin protects from senescence and fibrosis during renal aging by stabilizing YB-1 and ensuring cell cycle progression.

BACKGROUND:Although miR-216a-5p is linked to tumour progression and chemoresistance, its mechanistic contributions to gastric cancer (GC) remain undefined. This study sought to clarify the role of miR-216a-5p in GC progression and its impact on oxaliplatin (OXA) resistance. METHODS:MiR-216a-5p expression in GC specimens and cell lines was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatics and dual-luciferase reporter assays were employed to identify and, subsequently, validate ZBTB2 as a direct target of miR-216a-5p, which was further confirmed through RNA immunoprecipitation, Western blot, and qRT-PCR analyses. In vitro functional assays, including proliferation, migration, and drug sensitivity assays, assessed the effects of miR-216a-5p and ZBTB2 on GC cells. Rescue experiments further elucidated the miR-216a-5p/ZBTB2 regulatory axis. Additionally, in vivo experiments substantiated these findings. RESULTS:Quantitative analyses revealed substantial downregulation of miR-216a-5p in both clinical GC samples and cellular models relative to matched non-neoplastic mucosal tissues and normal epithelial controls. Functional assays demonstrated that miR-216a-5p inhibited GC cell proliferation and migration while enhancing their sensitivity to OXA. Mechanistically, miR-216a-5p directly targeted and downregulated ZBTB2, thereby modulating GC cell growth and chemoresistance. Rescue experiments confirmed that ZBTB2 overexpression partially reversed the effects of miR-216a-5p on GC cells. In vivo studies further supported the tumour-suppressive role of miR-216a-5p and its regulation of ZBTB2. CONCLUSION:This study demonstrated that miR-216a-5p suppresses GC by inhibiting cell proliferation, migration, and OXA resistance through the downregulation of ZBTB2. Our findings underscored miR-216a-5p's role as a potential molecular target for improving chemotherapy efficacy against GC.

In response to tubular cell injury, the injured tubular cells undergoing apoptosis initiate the progression of renal fibrosis by releasing profibrotic factors and mediating intercellular communications. However, the regulatory mechanisms underlying tubular cell apoptosis remain elusive. In this study, we found that METTL3, the core methyltransferase of RNA N6-methyladenosine (m6A) modification, is significantly increased in tubular cells in various renal fibrosis models. Knockdown of METTL3 ameliorated ischemia-reperfusion injury (IRI)- and unilateral ureteral obstruction (UUO)- induced renal fibrosis in mice. Transcriptome sequencing analysis revealed a causal role METTL3 in promoting CXCL10 expression and activating the proapoptotic pathways in tubular epithelial cells (TECs). Our mechanistic study showed that METTL3-catalzed m6A modification of CXCL10 mRNA increased mRNA stability, and, thus, led to the upregulation of CXCL10 in the injured TECs both in vitro and in vivo. While CXCL10 induced the apoptosis of TECs at a time- and dose-dependent manner, application of neutralizing antibody against CXCL10 significantly suppressed the METTL3-mediated apoptosis of TECs, and protected TECs from H2O2- and cisplatin-induced apoptosis as well. Finally, heterozygous deletion of METTL3 in vivo protected the mice from renal fibrosis through suppressing tubular cell apoptosis, but systemic administration of CXCL10 abolished the protective effect of METTL3 deletion on tubular cell apoptosis and subsequent renal fibrosis. In conclusion, our findings identify the METTL3/CXCL10 axis and its proapoptotic functions on TECs as an important pathogenic cause of renal fibrosis, thereby suggesting a potential therapeutic option in kidney diseases.

Inflammation is a key factor that contributes to cartilage degeneration in osteoarthritis (OA). p-Synephrine has anti-inflammatory effects. Nevertheless, the effects of p-synephrine on OA remain to be elucidated. The objective is to explore the effects of p-synephrine on OA. First, cell counting kit-8 (CCK-8) assay and flow cytometry were used to assess the effects of p-synephrine on chondrocyte viability and apoptosis. Then, Western blot and quantitative real time-PCR (qRT-PCR) were employed to determine the expressions of matrix metalloproteinase-1 (MMP-1), MMP-3, and MMP-13, as well as collagen II and aggrecan, in OA chondrocytes induced by interleukin-1β (IL-1β). Furthermore, we created an injectable gelatin methacrylamide (Gelma) hydrogel incorporating p-synephrine and conducted evaluations of its drug release profile and the degradation properties of hydrogels, aiming to optimize the intra-articular application of p-synephrine in the mouse OA model. Finally, cartilage degradation was analyzed using safranine O and fast green staining. In vitro, p-synephrine protected chondrocytes and effectively inhibited IL-1β-induced chondrocyte apoptosis. Moreover, p-synephrine inhibited the expressions of MMP-1, MMP-3, and MMP-13, and increased the expressions of collagen II and aggrecan. p-Synephrine might exert its biological effects by suppressing the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. Gelma hydrogels with different degrees of amination could control the release rate of p-synephrine due to differences in their pore structure and degradation rates. Among these, Gelma 90 achieved a more stable and sustained p-synephrine release. In vivo, p-synephrine loaded by injectable Gelma hydrogel thwarted cartilage deterioration. In summary, p-synephrine may exhibit chondroprotective effects by suppressing the MAPK and NF-κB signaling pathways, providing a new treatment for OA.

Tumor-associated macrophages (TAMs) play key roles in tumor progression and therapy resistance. In colorectal cancer (CRC), TAM heterogeneity challenges macrophage-targeted therapies, with certain antitumor macrophage subpopulations not yet fully characterized. This study bridges this gap by identifying a distinct subset of tumoricidal CD169+ macrophages. Increased infiltration of CD169+ macrophages was observed in CRC tissues, which was significantly associated with improved overall survival in patients with CRC. Deleting CD169+ macrophages in genetically engineered mouse models (MC38 orthotopic/ectopic and CD169DTR/+ApcMin/+ intestinal adenoma) accelerated tumor growth. Integrated multi-omics data and functional assays, including cell coculture models and animal experiments with antibody blockade, reveal an antitumor mechanism in which CD169+ macrophages directly interact with CRC cells. This interaction, mediated by CD169/CD43 molecular engagements, leads to tumor cell apoptosis via high levels of factor-related apoptosis ligand (FasL). Our results not only deepen our understanding of the CRC tumor microenvironment but also open avenues for cancer immunotherapy targeting.

The development of functional endothelial monolayers on synthetic vascular grafts remains challenging, particularly for small-diameter vessels (<6 mm) prone to thrombosis. Here, we present a pharmacological strategy combining 8-(4-chlorophenylthio) adenosine 3′,5′-cyclic monophosphate sodium salt (pCPT-cAMP, a tight junction promoter) with nitric oxide/cGMP pathway agonists 3-morpholinosydnonimine (SIN-1), captopril, and sildenafil) to enhance endothelialization. In human umbilical vein endothelial cells (HUVECs), this four-agent cocktail induced a flat, extended phenotype with a 3-fold increased cell area and 57.5% fewer cells required for surface coverage compared to controls. Immunofluorescence analysis revealed enhanced ZO-1 expression and continuous tight junction formation, while sustained nitric oxide (NO) production (3.9-fold increase) and restored prostacyclin (PGI2) secretion demonstrated preserved endothelial functionality. Anticoagulation assays confirmed a significant reduction in thrombus formation (p < 0.01) via dual inhibition of platelet activation and thrombin binding. These findings establish a synergistic drug combination that promotes rapid endothelialization while maintaining antithrombogenic activity, offering a promising solution for small-diameter vascular grafts. Further studies should validate long-term stability and translational potential in preclinical models.

Intraportal islet transplantation for treating insulin-dependent diabetes mellitus has been clinically validated. However, the hypoxic environment and sinusoidal architecture of the liver are unsuitable for the long-term survival of transplanted islets, leading to the loss of therapeutic effects within a year. The spleen has oxygen levels that meet islet needs, but intense instant blood-mediated inflammatory reactions (IBMIR) and low extracellular matrix (ECM) concentrations hinder islet engraftment and survival. In this study, we developed constructs of islets encapsulated by hepatocytes and fibroblasts. The hepatocytes and fibroblasts create a protective coating that reduces IBMIR due to the low expression of von Willebrand factor (vWF) in hepatocytes and supports normal islet survival through ECM production by fibroblasts. These constructs can be easily injected into the mouse spleen. The hepatocyte-fibroblast encapsulation significantly reduces islet mortality during the post-transplantation stress period, enabling rapid engraftment and vascularization in the spleen. The spleen's high-oxygen environment then supports long-term (over one year) islet survival and sustained glycemic regulation. Additionally, this method significantly lowers the critical islet dose required for transplantation. The live-cell shielding strategy developed in this study represents a novel approach for islet transplantation and functional regeneration, demonstrating promising clinical potential.

Polychlorinated biphenyls (PCBs), a typical type of persistent organic pollutants (POPs), were previously widely employed as insulating and heat exchange fluids in transformers and capacitors. Despite knowledge of its adverse effects, the precise mechanism underlying PCB77 toxicity remains enigmatic. In this study, we utilized zebrafish as a model organism to explore the toxic effects of various concentrations of PCB77 (10, 200, and 1000 μg/L) and its molecular toxicity mechanisms. Upon exposure to dosages of PCB77 throughout embryonic and larval stages, the zebrafish exhibited adverse phenotypic manifestations, including deformities, decreased heart rates, increased distances between the bulbus arteriosus (BA) and sinus venosus (SV) and reduced locomotor ability. Transcriptome analysis revealed the common enriched pathways across all PCB77 concentration groups, such as retinol metabolism, steroid hormone biosynthesis, and metabolism of xenobiotics by cytochrome P450, which are closely related to the activity of cytochrome P450 (cyp1a) enzymes. Furthermore, Adverse Outcome Pathway (AOP) framework which integrates AOPs and dose-dependent transcriptomics to predict PCB77-induced adverse outcomes (AOs) revealed that aryl hydrocarbon receptor (AhR) associated AOPs triggered by PCB77 exposure may increase early-life stage mortality and decrease cardiac development, indicating that the primary toxic pathways of PCB77 in zebrafish may involve AhR-mediated signaling. Besides, molecular docking modeling demonstrated that PCB77 could bind to the groove within the AhR domain, suggesting that PCB77 induces embryotoxicity in zebrafish through its interaction with AhR. Collectively, these findings not only deliver a thorough examination of PCB77-induced developmental toxicity as well as the underlying mechanisms, but also validate the efficacy of the analytical approach leveraging AOP framework in unraveling toxicity mechanisms of environmental contaminants, which holds promise for risk assessment associated with novel environmental pollutants.

Peritubular capillary (PTC) rarefaction is a common pathological feature of chronic kidney disease (CKD). The critical function of PTCs in maintaining blood supply for tubular epithelial cells renders PTCs a promising therapeutic target. However, the role of PTC rarefaction in the progression of kidney fibrosis remains elusive. In this study, we first characterized mice with altered PTC density. CD31 staining, together with microvascular network perfusion with FITC‐labelled albumin and laser speckle contrast imaging, revealed a significant increase in PTC density in Flt1 heterozygous‐deficient mice, whereas homozygous disruption of the plasminogen activator, urokinase receptor gene ( Plaur/uPAR ), led to a notable decrease in PTC density. Using these genetically distinct mice, we showed that preexisting higher PTC density protected against tubular injury and attenuated the progression of tubulointerstitial fibrosis in two distinct kidney injury models, namely, ischemia–reperfusion injury (IRI) and unilateral ureteral obstruction (UUO). By contrast, Plaur ‐deficient mice with established lower PTC density displayed exacerbated tubular injury and renal fibrosis when subjected to IRI or UUO. The pathophysiological significance of PTC density was associated with protective effects on tubular cell apoptosis and concomitant regeneration. Finally, vasodilation of the renal capillary with minoxidil, a clinically available drug, effectively prevented UUO‐induced tubular injury and renal fibrosis. Moreover, minoxidil treatment abolished the detrimental effect of Plaur deficiency on the UUO‐treated kidney, thus suggesting a causative role of PTC density in the susceptibility of Plaur knockout mice to tubular injury following fibrosis. Our results provide an overview of the pathologic significance of PTC density alterations in the progression of CKD, and show that improving peritubular microcirculation is effective in preventing tubular injury and the subsequent renal fibrosis. © 2025 The Pathological Society of Great Britain and Ireland.

Precise neoepitope discovery is crucial for effective cancer therapeutic vaccines. Conventional approaches struggle to build a repertoire with sufficient immunogenic epitopes. We developed a workflow leveraging full-length ribosome-nascent chain complex-bound mRNA sequencing (FL-RNC seq) and artificial intelligence-based predictive models to accurately identify the neoepitope landscape, especially large-scale transcript variants (LSTVs) missed by short-read sequencing. In the MC38 mouse model, we identified 22 LSTV-derived neoepitopes encoded by a synthesized mRNA lipid nanoparticle vaccine. As a standalone therapy and combined with anti-PD-1 immunotherapy, the vaccine curbed tumor progression, induced robust T cell-specific immunity, and modulated the tumor microenvironment. This underscores the multifaceted potentials of LSTV-derived vaccines. Our approach expands the neoepitope source repertoire, offering a method for discovering personalized cancer vaccines applicable to a broader tumor range. The results highlight the importance of comprehensive neoepitope identification and the promise of LSTV-based vaccines for cancer immunotherapy.

Adoptive cell therapies for solid tumors face persistent challenges from poor tumor infiltration and immunosuppressive microenvironment. To overcome these limitations, a clinically scalable platform is developed to generate chimeric antigen receptor macrophages (CAR-HMs) from tamoxifen-regulated immortalized Hoxb8-transduced myeloid progenitors, achieving >95% CAR transduction efficiency and 60-fold expansion within 10 days. Engineered with a colorectal cancer-specific anti-carcinoembryonic antigen (CEA) CAR, these FcγRI-CAR-HMs demonstrated potent tumoricidal activity (>80% CRC cell lysis in vitro), deep tissue penetration (>100 µm in 3D tumor spheroids), and significant therapeutic efficacy (≈89% tumor regression in vivo). Mechanistic studies demonstrated that FcγRI-CAR-HMs remodeled the tumor microenvironment through direct tumor phagocytosis, T cells recruitment and activation, and synergistic enhancement of anti-PD-1 therapy in colorectal cancer models, while an integrated inducible caspase-9 (iCas9) suicide switch ensured safety without compromising long-term persistence. This progenitors-based platform not only addresses critical manufacturing challenges but also unlocks the full therapeutic potential of CAR-macrophages, whose unique ability to synergize with checkpoint inhibitors provides a transformative approach for treatment-refractory solid tumors.

The induction of apoptosis in tumor cells is a common target for the development of anti-tumor therapies; however, these therapies still leave patients at increased risk of disease recurrence. For example, apoptotic tumor cells can promote tumor growth and immune evasion via the secretion of metabolites, apoptotic extracellular vesicles, and induction of pro-tumorigenic macrophages. This paradox of apoptosis induction and the pro-tumorigenic effects of tumor cell apoptosis has begged the question of whether apoptosis is a suitable cancer therapy, and led to further explorations into other immunogenic cell death-based approaches. However, these strategies still face multiple challenges, the most critical of which is the tumor microenvironment. Contrary to the promotion of immune tolerance mediated by apoptotic tumor cells, apoptotic bodies with enriched tumor-related antigens have demonstrated great immunogenic potential, as evidenced by their ability to initiate systemic T-cell immune responses. These characteristics indicate that apoptotic body-based therapies could be ideal "in situ" extra-tumoral tumor vaccine candidates for the treatment of cancers, and further address the current issues with apoptosis-based or immunotherapy treatments. Although not yet tested clinically, apoptotic body-based vaccines have the potential to better treatment strategies and patient outcomes in the future.

Intestinal fibrosis, a severe complication of Crohn's disease (CD), is linked to chronic inflammation, but the precise mechanism by which immune-driven intestinal inflammation leads to fibrosis development is not fully understood. This study investigates the role of myeloid-derived suppressor cells (MDSCs) in intestinal fibrosis in CD patients and a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse model. Elevated MDSCs are observed in inflamed intestinal tissues prior to fibrosis and their sustained presence in fibrotic tissues of both CD patients and murine models. Depletion of MDSCs significantly reduces fibrosis, highlighting their key role in the fibrotic process. Mechanistically, MDSC-derived mCCL6 activates fibroblasts via the CCR1-MAPK signaling, and interventions targeting this axis, including neutralizing antibodies, a CCR1 antagonist, or fibroblast-specific Ccr1 knockout mice reduce fibrosis. In CD patients with stenosis, human CCL15, analogous to mCCL6, is found to be elevated in MDSCs and activated fibroblasts. Additionally, CXCR2 and CCR2 ligands are identified as key mediators of MDSC recruitment in intestinal fibrosis. Blocking MDSC recruitment with CXCR2 and CCR2 antagonists alleviates intestinal fibrosis. These findings suggest that strategies targeting MDSC recruitment and mCCL6/hCCL15 signaling could offer therapeutic benefits for intestinal fibrosis.

Alcoholic liver disease (ALD) is a common chronic redox disease caused by increased alcohol consumption. Abstinence is a major challenge for people with alcohol dependence, and approved drugs have limited efficacy. Therefore, this study aimed to explore a new treatment strategy for ALD using ferroferric oxide endohedral fullerenol (Fe3O4@C60(OH)n) in combination with static magnetic and electric fields (sBE). The primary hepatocytes of 8-9-week-old female BALB/c mice were used to evaluate the efficacy of the proposed combination treatment. A mouse chronic binge ethanol feeding model was established to determine the alleviatory effect of Fe3O4@C60(OH)n on liver injury under sBE exposure. Furthermore, the ability of Fe3O4@C60(OH)n to eliminate •OH was evaluated. Alcohol-induced hepatocyte and mitochondrial damage were reversed in vitro. Additionally, the combination therapy reduced liver damage, alleviated oxidative stress by improving antioxidant levels, and effectively inhibited liver lipid accumulation in animal experiments. Here, we used a combination of magnetic derivatives of fullerenol and sBE to further improve the ROS clearance rate, thereby alleviating ALD. The developed combination treatment may effectively improve alcohol-induced liver damage and maintain redox balance without apparent toxicity, thereby enhancing therapy aimed at ALD and other redox diseases.

Full-thickness skin grafts often face challenges related to inefficient vascularization in clinical settings. Senescent cells, known for secreting various growth factors, have demonstrated excellent effects on angiogenesis. In this study, we induced senescence in a subset of fibroblasts in the donor dermis by co-administering trametinib and palbociclib before harvesting the skin grafts for transplantation. Grafts containing these senescent fibroblasts showed significant promotion of vascularization when surgically transplanted into recipient animals. This approach resulted in a 100% survival rate of the transplanted skin. Additionally, the senescent fibroblasts optimized wound healing and matrix remodeling, subsequently reducing inflammation and scar hyperplasia. Importantly, these senescent fibroblasts disappeared 14 days post-grafting, preventing excessive accumulation of senescent cells. Overall, our study indicates that inducing senescence in the donor dermis prior to transplantation is an effective strategy to enhance vascularization and increase the success rate of skin grafting.

Liver fibrosis/cirrhosis is a pathological state caused by excessive extracellular matrix deposition. Sustained activation of hepatic stellate cells (HSC) is the predominant cause of liver fibrosis, but the detailed mechanism is far from clear. In this study, we found that long noncoding RNA Fendrr is exclusively increased in hepatocytes in the murine model of CCl4- and bile duct ligation-induced liver fibrosis, as well as in the biopsies of liver cirrhosis patients. In vivo, ectopic expression of Fendrr aggravated the severity of CCl4-induced liver fibrosis in mice. In contrast, inhibiting Fendrr blockaded the activation of HSC and ameliorated CCl4-induced liver fibrosis. Our mechanistic study showed that Fendrr binds to STAT2 and enhances its enrichment in the nucleus, which then promote the expression of interleukin 6 (IL-6), and, ultimately, activates HSC in a paracrine manner. Accordingly, disrupting the interaction between Fendrr and STAT2 by ectopic expression of a STAT2 mutant attenuated the profibrotic response inspired by Fendrr in the CCl4-induced liver fibrosis. Notably, the increase of Fendrr in patient fibrotic liver is positively correlated with the severity of fibrosis and the expression of IL-6. Meanwhile, hepatic IL-6 positively correlates with the extent of liver fibrosis and HSC activation as well, thus suggesting a causative role of Fendrr in HSC activation and liver fibrosis. In conclusion, these observations identify an important regulatory cross talk between hepatocyte Fendrr and HSC activation in the progression of liver fibrosis, which might represent a potential strategy for therapeutic intervention.