2. Academic Validation
  3. DN203316, a novel PPARδ agonist, suppresses ferroptotic signaling and fibrogenesis in metabolic dysfunction-associated steatohepatitis

DN203316, a novel PPARδ agonist, suppresses ferroptotic signaling and fibrogenesis in metabolic dysfunction-associated steatohepatitis

  • Exp Mol Med. 2026 Jun 5. doi: 10.1038/s12276-026-01740-0.
Ye Jin Kim # 1 2,  Jina Kim # 3,  Da Young An 4,  Mihyang Park 1 2,  Gui-Hwa Jeong 5,  Jonghwa Jin 1 2,  Mi Kyung Kim 6,  Jungwook Chin 7,  Yeon-Kyung Choi 8 9,  Keun-Gyu Park 10 11 12
Affiliations

Affiliations

  • 1 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • 2 Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
  • 3 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea.
  • 4 Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea.
  • 5 Departmentof Internal Medicine, CHA Gumi Medical Center, CHA University, Gumi, Republic of Korea.
  • 6 Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
  • 7 Cureverse, KIST, Seoul, Republic of Korea. [email protected].
  • 8 Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea. [email protected].
  • 9 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea. [email protected].
  • 10 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea. [email protected].
  • 11 Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea. [email protected].
  • 12 Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 42249087 DOI: 10.1038/s12276-026-01740-0
Abstract

Recently, Ferroptosis has emerged as a pathogenic mechanism that drives metabolic dysfunction-associated steatohepatitis (MASH); however, the upstream triggers and their relevance to fibrosis remain poorly understood. Here we identified dietary cholesterol-induced Ferroptosis and the downregulation of Peroxisome Proliferator-activated Receptor delta (PPARδ) as central drivers of MASH pathogenesis. To investigate this, human liver samples and cholesterol-enriched dietary murine models of MASH were examined in parallel with mechanistic studies in hepatocytes and hepatic stellate cells (HSCs). Cholesterol-induced MASH was associated with pronounced hepatic lipid peroxidation and the selective downregulation of PPARδ. The loss of PPARδ disrupted redox homeostasis and sensitized hepatocytes to Ferroptosis, whereas exosomal double-stranded DNA released from ferroptotic hepatocytes activated STING-TBK1-IRF3 and induced expression of profibrotic genes in HSCs. These effects were reversed by either overexpression of hepatocyte-specific PPARδ or pharmacologic treatment with DN203316, a novel and highly selective PPARδ Agonist. In vivo, DN203316 mitigated Ferroptosis, inflammation and fibrosis without inducing metabolic derangement. These findings were substantiated by clinical data demonstrating a marked increase in lipid peroxidation and STING-driven HSC activation in liver tissues from patients with MASH. In conclusion, PPARδ is a key regulator of cholesterol-induced Ferroptosis and exosome-mediated fibrogenic signaling in MASH. DN203316 offers a promising therapeutic strategy to suppress Ferroptosis, disrupt hepatocyte-HSC crosstalk and attenuate disease progression.

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