2. Academic Validation
  3. Structurally diverse tetrahydroxanthone analogues from Paraconiothyrium sp. AC31 with pyroptosis induction through targeted inhibition of PARP1 in hepatocellular carcinoma cells

Structurally diverse tetrahydroxanthone analogues from Paraconiothyrium sp. AC31 with pyroptosis induction through targeted inhibition of PARP1 in hepatocellular carcinoma cells

  • Bioorg Chem. 2025 Feb 26:157:108310. doi: 10.1016/j.bioorg.2025.108310.
Meng-Ke Zhang 1,  Qiao-Qiao Hu 2,  Li-Ming He 3,  Mu Li 4,  Wei-Chen Chen 3,  Kong-Kai Zhu 5,  Rui-Ying Yuan 6,  Xiao-Yan Wu 7,  Ping Gao 8,  Xiao-Bin Zeng 9,  You-Sheng Cai 10
Affiliations

Affiliations

  • 1 Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China; Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China.
  • 2 School of Pharmacy, Guangdong Medical University, Dongguan 523808, People's Republic of China.
  • 3 Department of Nephrology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China; Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China.
  • 4 Department of Nephrology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China; Department of Medicament, College of Medicine, Tibet University, Lhasa, People's Republic of China.
  • 5 Advanced Medical Research Institute, Shandong University, Jinan 250012, People's Republic of China.
  • 6 Department of Medicament, College of Medicine, Tibet University, Lhasa, People's Republic of China.
  • 7 Department of Nephrology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China.
  • 8 Department of Nephrology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China. Electronic address: tgzy1017@163.com.
  • 9 School of Pharmacy, Guangdong Medical University, Dongguan 523808, People's Republic of China; Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen 518120, Guangdong Province, People's Republic of China; Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, People's Republic of China. Electronic address: zeng.xiaobin@szhospital.com.
  • 10 Department of Nephrology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China; Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China. Electronic address: cysh2002@whu.edu.cn.
PMID: 40024197 DOI: 10.1016/j.bioorg.2025.108310
Abstract

This study reports the isolation and characterization of six novel tetrahydroxanthone derivatives, paraconixanthones A - F (1-6), a new diphenyl ether (7), and thirteen known compounds (8-20) from the endophytic fungus Paraconiothyrium sp. AC31. The chemical structures were elucidated using NMR, MS, X-ray diffraction, and ECD analyses. Paraconixanthones A and B (1 and 2) represent the first examples of tetrahydroxanthone-benzoate dimers, suggesting a unique biosynthetic pathway. Compound 12 exhibited potent anti-proliferative activity against HepG2 hepatocellular carcinoma cells (IC50 = 1.19 μM), outperforming the standard therapy lenvatinib. Mechanistic studies revealed that compound 12 inhibits PARP1, leading to DNA damage, ROS accumulation, and Caspase-3/GSDME-mediated Pyroptosis. Additionally, it induces intrinsic Apoptosis through Bax/Bcl-2 modulation and caspase-7 activation. Meanwhile, GSDME deficiency treated with 12 exhibited the increased levels of PARP1 and Caspase-3, supporting the cell death induced by 12 shifted from Pyroptosis to Apoptosis. These findings highlight the therapeutic potential of tetrahydroxanthones as selective agents targeting multiple cell death pathways in hepatocellular carcinoma, expanding the scope of natural product-based anti-cancer strategies.

Keywords

Caspase-3/GSDME pathway; Hepatocellular carcinoma; PARP inhibitor; Paraconiothyrium sp.; Pyroptosis; Reactive oxygen species (ROS); Tetrahydroxanthone.

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