Targeting PNPLA3 to Treat MASH and MASH Related Fibrosis and Cirrhosis

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by metabolic triggers and genetic predisposition. Among the genetic MASLD risk variants identified today, the common PNPLA3 148M variant exerts the largest effect size of MASLD heritability. The PNPLA3 148M protein is causatively linked to the development of liver steatosis, inflammation and fibrosis in experimental studies and is therefore an appealing target for therapeutic approaches to treat this disease. Several PNPLA3 targeted approaches are currently being evaluated in clinical trials for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), the most severe form of MASLD and promising proof of principle data with reduced liver fat content in homozygous PNPLA3 148M risk allele carriers has been reported from phase 1 trials following hepatic silencing of PNPLA3. Thus, targeting PNPLA3, the strongest genetic determinant of MASH may hold promise as the first precision medicine for the treatment of this disease. A histological endpoint-based phase 2b study has been initiated and several more are expected to be initiated to evaluate treatment effects on histological MASH and liver fibrosis in participants being homozygous for the PNPLA3 148M risk allele variant. The scope of this mini-review is to briefly describe the PNPLA3 148M genetics, function and preclinical experimental evidence with therapeutic approaches targeting PNPLA3 as well as to summarise the PNPLA3 based therapies currently in clinical development.

Keywords: MASH; MASLD; NAFLD; NASH; PNPLA3; SLD; metALD; precision medicine; steatotic liver disease.

FIGURE 1

PNPLA3 targeting strategies in clinical development and proposed hepatocyte mechanisms in MASH. Silencing or modulation of PNPLA3 in PNPLA3 148M risk allele carriers lead to: (1) increased availability of the joint co‐activator ABHD5 for ATGL activation leading to an increased lipid remodelling in lipid droplets, (2) increased PUFAs in VLDL triglycerides, (3) decreased STAT3 and NF‐κB activation leading to (4) decreased levels of IL6 and hsCRP, inflammation and fibrosis. ABHD5, 1‐acylglycerol‐3‐phosphate O‐acyltransferase; ASGPR1, asialoglycoprotein receptor 1; ASO, antisense oligonucleotide; GalNAc, N‐acetylgalactosamine; hsCRP, high‐sensitivity C‐reactive protein; IL6, interleukin 6; MASH, metabolic dysfunction‐associated steatohepatitis; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; PNPLA3, patatin‐like phospholipase domain‐containing protein 3; PUFA‐TG, polyunsaturated fatty acids in triglycerides; RNaseH1, Ribonuclease H1; RISC, RNA‐induced silencing complex; siRNA, small interfering RNA; STAT3, signal transducer and activator of transcription 3; VLDL, very low‐density lipoprotein. Created with BioRender.com.