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
  • 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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