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.

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-HS4,5^Tg mice, Loxl1 ^fl/fl Gfap ^Cre 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.

Objective To determine the impact of a solitary lifestyle on health-related quality of life (HRQoL) in adults with obstructive sleep apnea (OSA). Methods This was a prospective cohort study; patients diagnosed with OSA but not receiving continuous positive airway pressure (CPAP) therapy were enrolled in our study. These participants completed basic information and the Short Form-36 Health Survey (SF-36) at baseline and were divided into the living alone and living with others groups. Telephone follow-up was performed 1 year later to re-evaluate the SF-36. Differences in health status between and within groups were assessed. In addition, variables associated with changes in the health of the whole population were examined. Results A total of 402 patients with OSA were enrolled, including 120 in the living alone group and the rest in the living with others group. After a year, mental health scores of the living alone group decreased (55.7 ± 21.5 versus 54.1 ± 22.7, p = 0.001), while physical functioning scores of the living with others group increased significantly (82.1 ± 24.7 versus 82.6 ± 24.2, p = 0.006). In the whole population, the determinants of mental health change after 1 year from baseline were alcohol drinking (beta coefficient − 1.169, 95% CI − 2.03 to − 0.309, p = 0.008) and solitary living (beta coefficient − 1.135, 95% CI − 2.072 to − 0.199, p = 0.018). Conclusion Regarding all initial variables, alcohol drinking and solitary living seem to be the predictors of mental health change of patients with OSA in China. We speculate that to improve the quality of life of such people, the medical staff could provide certain social support for them.