Histological and molecular responses to pemafibrate in MASLD with hypertriglyceridemia: the CLARITY study

Background & Aims: The histological effects and underlying molecular responses to pemafibrate in MASLD remain poorly defined. We investigated longitudinal histological changes and cell-type-specific molecular responses in patients with MASLD and hypertriglyceridemia. Methods: In the prospective, single-arm CLARITY study, 33 patients with MASLD and hypertriglyceridemia received pemafibrate (0.2 mg/day) and underwent paired liver biopsies at baseline and 52 weeks. Primary outcomes were changes in fibrosis stage and NAFLD activity score (NAS). Complementary analyses included dual-energy X-ray absorptiometry, pooled liver single-nucleus RNA sequencing, paired hepatic qPCR, and circulating proteomics. An external mouse transcriptomic dataset was analysed to investigate the contribution of hepatocyte PPARα. Results: Fibrosis stage improved in 16 of 33 patients (48.5%), remained unchanged in 16, and worsened in one; 13 patients (39.4%) achieved fibrosis improvement without NAS worsening. Both fibrosis stage and NAS decreased significantly (P<0.001 and P=0.003, respectively). ALT decreased from 64 to 28 U/L and triglycerides from 169 to 90 mg/dL (both P<0.001), without significant changes in body weight or DXA-derived body composition. Single-nucleus profiling revealed increased hepatocyte PPARα/fatty acid oxidation-associated transcriptional scores and reduced fibrogenic extracellular matrix and inflammatory programmes in HSCs/fibroblasts and macrophages/Kupffer cells, respectively. Paired hepatic qPCR confirmed reductions in COL1A1, THBS2, DCN, TIMP1 and TREM2, together with increased HMGCS2. Circulating proteomics revealed increased FGF21 and decreased DCN, IL1B, and CXCL8 levels. In external mouse data, selected metabolic transcriptional responses were attenuated by hepatocyte-specific PPARα deletion. Conclusions: Pemafibrate treatment was associated with histological improvement and coordinated, cell-type-specific metabolic and fibro-inflammatory remodelling in MASLD with hypertriglyceridemia. Convergent human tissue and circulating molecular findings, supported by external genetic evidence, implicate hepatocyte PPARα-related pathways in these responses.