Cell Biology, Aging, Cancer Research, Molecular Biology
2
Scopus Publications
Scopus Publications
Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH Xiaodong Yu, Chenyuan Huang, Martijn Evers, Jingjing Liu, Hui Jun Ting, Sitong Zhang, Suet Yen Chong, Michelle Siying Tan, Siyu Wang, Nilofer Sayed, Liang Gao, Mark D. Muthiah, Gwyneth S. T. Soon, Aileen Wee, Edward Kai-Hua Chow, Natalie Jun Hui Soh, Giorgia Pastorin, Victor C. Yu, Bin Liu, Yock Young Dan, Federico Torta, Raymond Schiffelers, Gert Storm, Jiong-Wei Wang Science Advances, 2025 Increasing evidence implicates ceramides in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). However, the therapeutic potential of liver-targeted ceramide lowering remains unclear. In this study, we demonstrate that elevated ceramide levels in MASH patients and mouse models are closely associated with the activation of hepatic de novo ceramide synthesis. The analysis of human hepatic single-nucleus RNA sequencing (snRNA-seq) data revealed predominant up-regulation of SPTLC2 , which encodes a subunit of the rate-limiting enzyme in the de novo ceramide synthesis pathway, in hepatocytes. By targeted inhibition of SPTLC2 with lipid nanoparticle–mediated siRNA delivery to hepatocytes, we reduced both hepatic and circulating ceramide levels. This intervention suppressed hepatic lipid uptake and lipogenesis, thereby alleviating MASH progression. Therapeutic efficacy was demonstrated in an 8-week methionine-choline–deficient diet-induced MASH model and validated in a 1-year choline-deficient high-fat diet–induced MASH model. Our findings highlight hepatocyte Sptlc2 as a promising therapeutic target for MASH.
p62/SQSTM1 in liver diseases: the usual suspect with multifarious identities Chong Teik Tan, Natalie Jun Hui Soh, Hao‐Chun Chang, Victor C. Yu FEBS Journal, 2023 p62/Sequestosome‐1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal pathway. Interestingly, p62 also serves as a signaling scaffold to participate in the regulation of multiple physiological processes, including oxidative stress response, metabolism, inflammation, and programmed cell death. Perturbation of p62 activity has been frequently found to be associated with the pathogenesis of many liver diseases. p62 has been identified as a critical component of protein aggregates in the forms of Mallory–Denk bodies (MDBs) or intracellular hyaline bodies (IHBs), which are known to be frequently detected in biopsy samples from alcoholic steatohepatitis (ASH), non‐alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC) patients. Importantly, abundance of these p62 inclusion bodies is increasingly recognized as a biomarker for NASH and HCC. Although the level of p62 bodies seems to predict the progression and prognosis of these liver diseases, understanding of the underlying mechanisms by which p62 regulates and contributes to the development and progression of these diseases remains incomplete. In this review, we will focus on the function and regulation of p62, and its pathophysiological roles in the liver, by critically reviewing the findings from preclinical models that recapitulate the pathogenesis and manifestation of these liver diseases in humans. In addition, we will also explore the suitability of p62 as a predictive biomarker and a potential therapeutic target for the treatment of liver diseases, including NASH and HCC, as well as recent development of small‐molecule compounds for targeting the p62 signaling axis.
