Histological and molecular responses to pemafibrate in MASLD with hypertriglyceridemia: the CLARITY study
- 1Department of Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Nagano, Japan; Consultation Center for Liver Diseases, Shinshu Univ
Abstract
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 PPAR. 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 PPAR/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 PPAR 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 PPAR-related pathways in these responses.
Related
- Dose-dependent efficacy and renal safety of pemafibrate versus fenofibrate in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia: a multicenter randomized controlled, open label trial
- Real-World Effects of Pemafibrate Extended-Release in Patients with Hypertriglyceridemia: A 12-Month Retrospective Study
- Reduction in Rheumatoid Factor and Matrix Metalloproteinase-3 With Successful Glucocorticoid Withdrawal After Initiation of Pemafibrate in a Patient With Rheumatoid Arthritis and Hypertriglyceridemia: A Case Report.
- Immunophenotypic Features of T-Lymphocyte Distribution Across Histological and Molecular Subtypes of Serous Ovarian Neoplasms: A Retrospective Immunohistochemical Study
- Patients with cyclops syndrome exhibit elevated synovial fluid interleukin‐6 (IL‐6) and tumor necrosis factor alpha (TNF‐α) levels and disorganized collagen remodelling within the lesion: A histological and molecular study
BibTeX
@misc{kimura2026histological,
title = {{Histological and molecular responses to pemafibrate in MASLD with hypertriglyceridemia: the CLARITY study}},
author = {T. Kimura and M. Iwaya and N. Tamaki and S.-i. Wakabayashi and T. Iwadare and K. Fujita and Y. Kamijo and Y. Kobayashi and T. Okumura and H. Kobayashi and Y. Yamashita and T. Yamazaki and T. Nakajima and T. Uehara and M. Kurosaki and N. Tanaka},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.26366915},
url = {https://www.medrxiv.org/content/10.64898/2026.10.30.26366915v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Histological and molecular responses to pemafibrate in MASLD with hypertriglyceridemia: the CLARITY study
AU - T. Kimura
AU - M. Iwaya
AU - N. Tamaki
AU - S.-i. Wakabayashi
AU - T. Iwadare
AU - K. Fujita
AU - Y. Kamijo
AU - Y. Kobayashi
AU - T. Okumura
AU - H. Kobayashi
AU - Y. Yamashita
AU - T. Yamazaki
AU - T. Nakajima
AU - T. Uehara
AU - M. Kurosaki
AU - N. Tanaka
PY - 2026
DA - 2026/10/30
PB - medRxiv
DO - 10.64898/2026.10.30.26366915
UR - https://www.medrxiv.org/content/10.64898/2026.10.30.26366915v1
AB - 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 PPAR. 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 PPAR/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 PPAR 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 PPAR-related pathways in these responses.
ER -