Triglyceride-lowering therapies for hepatic steatosis: mechanisms, efficacy, and clinical perspectives

Hepatic steatosis, the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), is closely associated with elevated plasma and intrahepatic triglyceride (TG) levels, often driven by insulin resistance, atherogenic dyslipidemia, and metabolic syndrome. Growing evidence suggests that triglyceride-lowering therapies may not only improve systemic lipid profiles but also directly impact hepatic fat accumulation and associated inflammation and fibrosis. This review explores current and emerging TG-lowering therapies, including fibrates, omega-3 fatty acids, pemafibrate, and novel agents such as pegozafermin (an FGF21 analog), and APOC3 and angiopoietin-like protein 3 (ANGPTL3) inhibitors, in the context of hepatic steatosis and MASLD. We discuss the mechanistic rationale behind TG-lowering as a therapeutic strategy, summarize key preclinical and clinical trial findings, and evaluate their effects on liver fat content, liver enzymes, fibrosis markers, and histologic outcomes. While several agents demonstrate promise in reducing intrahepatic fat deposition and improving liver-related outcomes, further large-scale studies are required to establish their long-term efficacy and safety, and potential for disease modification in MASLD/metabolic dysfunction-associated steatohepatitis (MASH). Triglyceride-targeted therapies may offer a valuable adjunct or complementary approach to current treatment paradigms focused on weight loss, insulin sensitization, and antagonizing inflammation.