Lecithin cholesterol acyltransferase (LCAT) plays a pivotal role in acyl-esterifying cholesterol intravascularly, but its function in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) has remained uncertain both in murine models and humans for decades, which is largely attributable to the distinct differences in cholesterol metabolism between mice and humans. Previously, we created a novel golden Syrian hamster model deficient in LCAT activity. Herein, we explored the influence of LCAT on the development of MASLD and MASH. A cross-sectional clinical study of LCAT activity and free cholesterol (FC) levels in healthy and MASLD patients was performed. LCAT knockout (LCAT KO) hamsters were used to explore the characteristics of cholesterol homeostasis and MASLD and MASH development. Lipidomics, mRNA-seq, and qPCR were employed to investigate the underlying mechanisms involved. MASLD patients displayed reduced LCAT activity, elevated FC levels, and ratio of FC/TC. Serum FC levels were positively correlated with triglyceride (TG), total cholesterol (TC), and apoB100 levels. In hamsters, LCAT deficiency resulted in increased FC levels and decreased high-density lipoprotein levels. Apolipoprotein profiles revealed increased ApoB100/48 and apoE but decreased apoAI. Increases in serum FC levels were primarily observed in LCAT-deficient hamster. Interestingly, LCAT KO hamsters presented mild TG species deposition in the liver even when fed a chow diet indicated by lipidomics. These increased TG species included TG (16:0/18:1/18:2), TG (16:0/18:1/18:3), and TG (16:0/16:1/18:1). On a high-fat and high-cholesterol diet, LCAT-deficient hamsters developed severe liver ballooning, inflammation, and fibrosis. Using HepG2 cells and primary hepatocytes confirmed that FC increased intracellular lipogenesis and promoted inflammatory response, which was reversed by a NLRP3 inhibitor. In summary, LCAT deficiency in hamsters promotes liver lipid deposition and MASH progression, thus highlighting the therapeutic role of LCAT in MASLD and MASH.

Chronic wounds present significant clinical challenges stemming from persistent inflammation, impaired angiogenesis, and disrupted tissue homeostasis. Nitric oxide (NO) and hydrogen sulfide (H2S) are important gaseous signalling molecules that play critical regulatory roles in the pathophysiology of numerous diseases. In the present study, we designed a novel prodrug, TSNO, which releases H2S and NO in a controlled manner under the catalysis of GSH and the engineered enzyme A4-β-GalH363A. Furthermore, a functional wound dressing was prepared by incorporating TSNO into an electrospun poly(ε-caprolactone) (PCL) mat, and the therapeutic efficacy was evaluated in a full-thickness skin wound model established in mice. Results showed that the functional wound dressing effectively accelerated the wound healing process by enhancing collagen synthesis, promoting angiogenesis, and regulating inflammation via controlled codelivery of H2S and NO. Taken together, the functional wound dressing developed in this study represents a promising candidate for treating large-scale skin wounds in the clinic.