We aimed to evaluate the usefulness of the Fibrosis-5 index (FIB-5) for predicting prognosis in patients with chronic heart failure and examine whether combining the Fibrosis-4 (FIB-4) and FIB-5 indices could enhance risk stratification in heart failure. This single-center retrospective cohort study analyzed data from an inpatient database. A total of 1,100 patients (mean age, 78 years; 58.2% male) were included. The primary endpoint was a composite event (all-cause mortality and rehospitalization for heart failure) within 1 year of hospital discharge, assessed before and after propensity score matching (PSM). Receiver operating characteristic curve analysis identified - 0.85 as the optimal FIB-5 cutoff value for predicting composite events, classifying patients into high- and low-FIB-5 groups. The low-FIB-5 group had significantly higher event rates than the high-FIB-5 group, both before and after PSM. A cubic spline curve analysis showed that lower FIB-5 values were associated with significantly higher composite event rates. In multivariable Cox regression analysis, low FIB-5 (< - 0.85) was significantly associated with the 1-year composite endpoint compared with the high-FIB-5 index. Among patients in the moderate-risk FIB-4 category, those with high FIB-5 values exhibited outcomes comparable to the low-risk FIB-4 group, whereas those with low FIB-5 values showed risks similar to the high-risk FIB-4 group. The FIB-5 index may serve as a useful prognostic marker in patients with chronic heart failure. Combining the FIB-4 and FIB-5 indices enables refined risk stratification by identifying high-risk individuals within the moderate-risk FIB-4 category using only routinely available laboratory parameters.

Muscle fibrosis is a major driver of progression in diverse myopathies, yet the conserved molecular mediators of this process in humans remain poorly defined. Here, we identify collagen VI as a common regeneration-impairing extracellular matrix (ECM) component across three distinct human myopathies: Duchenne Muscular Dystrophy (DMD), Oculopharyngeal Muscular Dystrophy (OPMD), and Inclusion Body Myositis (IBM). Proteomic profiling of fibrotic biopsies reveals consistent upregulation of collagen VI and laminin γ1, alongside disease-specific alterations. Fibroadipogenic progenitors (FAPs) are the predominant source of these ECM components, including collagen VI and laminin γ1. Functionally, xenotransplantation of patient-derived FAPs into regenerating mouse muscle induces localized collagen deposition, myofiber atrophy, and depletion of Pax7⁺ muscle stem cells. Mechanistic assays demonstrate that FAP-derived collagen VI is sufficient to impair myogenic fusion, while silencing COL6 in patient FAPs restores fusion capacity, directly linking pathological collagen VI deposition to regeneration failure. Our findings uncover collagen VI as a conserved effector of fibrosis and stem cell niche disruption in human myopathies, positioning it as a potential therapeutic target across genetically and clinically distinct muscle diseases.

Hepatic nerves have an underexplored role in liver function. The global prevalence of liver disease has reached unprecedented levels, with over 1.6 billion individuals affected by metabolic dysfunction-associated steatotic liver disease (MASLD). A comprehensive understanding of these liver disease mechanisms is essential for identifying the aetiologies of such conditions. Studies from the past 5 years suggest that hepatic nerves might influence the progression of MASLD to metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma. As MASLD advances, hepatic sympathetic activity increases while hepatic sympathetic innervation diminishes. Conversely, both parasympathetic and sympathetic innervation might contribute to hepatic fibrosis and liver dysfunction. This Review examines the function of hepatic neurons, their modulation by metabolic disease and the potential to target these mechanisms to develop novel treatments for liver diseases.

Myocardial ischaemia-reperfusion injury (MIRI) exacerbates cardiomyocyte damage through oxidative stress, inflammation, and apoptosis, limiting the efficacy of reperfusion therapies. We developed PB1-Lip@M-CST, a biomimetic nanoparticle comprising procyanidin B1 (PB1)-loaded liposomes coated with macrophage cell membranes and surface-functionalized with the cardiac-specific targeting peptide CSTSMLKAC (CST). The nanoparticles were characterized for hydrodynamic size, zeta potential, core-shell morphology, retention of macrophage surface proteins (CCR2, CD11b, CD36), high encapsulation efficiency, and sustained drug release. In vitro, PB1-Lip@M-CST markedly reduced phagocytic uptake by RAW 264.7 macrophages, enhanced internalization in HL-1 cardiomyocytes in a CST-dependent manner, and provided superior protection in CoCl2-induced hypoxia-reoxygenation models by suppressing reactive oxygen species, lipid peroxidation, proinflammatory cytokines, and apoptosis. Mechanistic studies using CXCR4-overexpressing HL-1 cells and Plerixafor-treated cells confirmed that these effects were mediated via modulation of the CXCR4-associated PI3K/AKT1 signaling pathway and restoration of the BAX/BCL-2 balance. In a mouse model of MIRI, intravenous administration of PB1-Lip@M-CST prolonged systemic circulation, with markedly enhanced cardiac accumulation (highest heart AUC) and improved therapeutic index, reduced infarct size to 25.58 ± 2.96% (versus 49.22 ± 3.03% in the model group), preserved left ventricular ejection fraction at 50.42 ± 8.74%, attenuated serum injury biomarkers, and inhibited long-term fibrosis and apoptosis, with an excellent biosafety profile. These findings establish PB1-Lip@M-CST as a novel biomimetic platform that integrates macrophage membrane-mediated immune evasion with CST-directed cardiac homing to achieve cardiac-targeted delivery of PB1 and subsequent CXCR4-dependent modulation of the PI3K/AKT1 pathway in MIRI.

Graphene-based collagen hydrogels have demonstrated anti-fibrotic potential in various diseases; however, their therapeutic efficacy in hypertrophic scars (HS) remains largely unexplored. Adipose stem cells (ASCs) and their extracellular vesicles have been shown to regulate HS progression, yet the role of ASCs derived apoptotic vesicles (ASCs-ApoVs) has not been fully investigated. In this study, we developed graphene-incorporated type I collagen cryogel (G-GEL(C)) and collected ASCs-ApoVs. We evaluated their individual and combined capacity to regulate HS and explored the potential of G-GEL(C) as a delivery system for ASCs-ApoVs. G-GEL(C) significantly inhibited fibrosis in HS derived fibroblasts (HS-fibroblasts), as evidenced by the downregulation of COL1A1 (p < 0.001 for both protein and mRNA), α-SMA (p < 0.001 for protein; p < 0.0001 for mRNA), and Vimentin (p < 0.05 for protein; p < 0.0001 for mRNA). Additionally, G-GEL(C) suppressed cell proliferation (p < 0.0001) and lateral migration (p < 0.001). Treatment with ASCs-ApoVs also reduced COL1A1 (p < 0.01 for protein; p < 0.0001 for mRNA) and α-SMA (p < 0.05 for both protein and mRNA), while Vimentin transcription was also downregulated (p < 0.001). G-GEL(C), characterized by high porosity and selective adsorption capacity for ASCs-ApoVs, enabled efficient loading and delivery of these vesicles. In vivo, G-GEL(C) loaded with ASCs-ApoVs decreased the scar elevation index (SEI) (p < 0.05), reduced α-SMA expression (p < 0.0001), locally increased 8-OHdG levels and raised the proportion of M2 macrophages, indicating effective regulation of HS. ASCs-ApoVs exhibit anti-fibrotic effects in HS. G-GEL(C) functions both as a direct modulator of HS-fibroblast phenotypes and as an efficient carrier for apoptotic vesicles. Collectively, they form a potent combinatorial system that significantly attenuates hypertrophic scar.

Immunotherapy has limited success in pancreatic ductal adenocarcinoma (PDAC) due to an immune exclusive tumor microenvironment (TME) that lacks many cytokines necessary for Natural Killer (NK) and T cell responses. Here, we design multiplexed mRNAs encoding interleukins, chemokines, and interferons as a safe and effective cytokine therapy for PDAC. Intratumoral injection of IL-12, IL-18, CCL5, CXCL10, and IFNβ mRNAs achieves robust yet transient cytokine expression, leading to NK and CD8+ T cell activation and reduced tumor growth and fibrosis in PDAC transplant mouse models. Combining cytokine with tumor antigen mRNAs enhances dendritic cell antigen presentation and CD8+ T cell priming locally and systemically that prolongs animal survival after a single dose. Remarkably, nanoparticle encapsulation of the cytokine/antigen mRNA cocktail allows systemic administration and local delivery to autochthonous PDAC tumors in mice, culminating in curative responses in 50% of animals and antigen-reactive T cell persistence. These results suggest that multiplexed mRNA approaches to deliver cytokines and antigens generally absent in the TME could pave the way for effective immunotherapy in PDAC.

Mechanical sensation has become a recent focus and key pathological driver of cardiac fibrosis. However, the crosstalk between major mechanosensitive cell and fibroblasts remains to be elucidated. In this study, single-cell temporal atlas of mechanosensitive ion channels is depicted in transverse aortic constriction male mouse heart. Piezo1 is the most abundant mechanosensitive ion channel and exhibits the highest expression in epicardial cells. Epicardial-specific Piezo1 knockout mice exhibit decreased fibrosis and cardiac dysfunction. Piezo1 mediates epithelial-mesenchymal transition only contributes to subepicardial fibrosis. Further functional experiments and human samples validation reveal that Piezo1 facilitates intraventricular fibroblast activation via the Chemerin-Cmklr1 paracrine signaling pathway. The activation of cardiac fibroblasts is mediated by Pi3k-Akt1-Pou3f1 pathway. The Cmklr1 inhibitor α-NETA effectively mitigates myocardial fibrosis and dysfunction, holding therapeutical potential. Collectively, this study untangles the global landscape of mechanosensitive channels and the spatiotemporal mechanism of epicardial cells to activate fibroblast via the Chemerin-Cmklr1 paracrine signaling pathway.

Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a rare inherited disorder caused by defects in the VPS33B trafficking protein, leading to impaired bile flow, progressive liver disease and early death. No effective treatments are currently available. Gene therapy offers a potential approach by restoring the missing VPS33B protein in liver cells. Here, we show that liver-targeted lentiviral gene therapy safely and effectively rescues key features of ARC syndrome in a mouse model following in vivo administration by intravenous injection, combined with transient liver macrophage depletion. To assess the treatment efficacy, disease severity is exacerbated by 0.25% cholic acid diet feeds. A liver-specific vector shows a favourable safety profile over a ubiquitous vector. Mice receiving the safe liver-specific vector display improved survival, growth and liver function, reduced fibrosis and bile canaliculi restoration. These findings support targeted gene therapy as a promising treatment for ARC syndrome and related early-onset liver diseases.