2. Academic Validation
  3. Identification of a novel HNF4α agonist regulating abnormal metabolism

Identification of a novel HNF4α agonist regulating abnormal metabolism

  • Eur J Med Chem. 2026 Sep 15:314:118864. doi: 10.1016/j.ejmech.2026.118864.
Tzumei Wang 1,  Chaochun Wei 1,  Jingwen Li 1,  Xinyi Zhao 1,  Kaixuan Wang 1,  Xing Peng 2,  Xiaodong Dou 1,  Yameng Liu 3,  Chao Wang 4,  Ning Jiao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, New Cornerstone Science Laboratory, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, New Cornerstone Science Laboratory, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, New Cornerstone Science Laboratory, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; Qingdao Rising Biotechnology Co., Ltd, Miaoling Rd, Qingdao, Shandong, 26606, China.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, New Cornerstone Science Laboratory, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, New Cornerstone Science Laboratory, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units, 15/F., Building 17W, 1503-1511, Hong Kong Special Administrative Region of China; State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. Electronic address: [email protected].
PMID: 42091004 DOI: 10.1016/j.ejmech.2026.118864
Abstract

Hepatocyte nuclear factor 4 alpha (HNF4α) is a key nuclear receptor involved in liver function and metabolic regulation, making it a potential therapeutic target for lipid-metabolism disorders. Combining time-resolved fluorescence resonance energy transfer (TR-FRET) high-throughput screening with a diffusion-based structure-guided generative design workflow (DiffSBDD), we identified and prioritized a series of compounds with HNF4α agonist-like activity. Among them, (Z)-19 showed good HNF4α activation with an EC50 of 9.2 μM, outperforming the reference agonist N-trans-caffeoyltyramine (NCT; EC50 = 129.6 μM). Surface plasmon resonance (SPR) supported a direct interaction with HNF4α (KD = 4.6 μM). In HepG2 cells, (Z)-19 reduced triglyceride and total Cholesterol accumulation with minimal cytotoxicity and exhibited ferroptosis-protective activity, with a response profile differing from that of NCT. In a hyperlipidemia mouse model, (Z)-19 lowered plasma triglyceride and total Cholesterol levels, indicating encouraging in vivo efficacy. Additionally, all-atom molecular dynamics (MD) simulations supported a possible binding mode characterized by persistent hydrogen-bonding and hydrophobic contacts within the ligand-binding domain, and yielded favorable binding-free-energy estimates consistent with the experimental potency ranking. Together, these results identify (Z)-19 as a promising starting point for further optimization and mechanistic investigation of compounds that modulate HNF4α.

Keywords

Abnormal metabolism; HNF4α; Molecular dynamics; Rational design; Synthesis.

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