2. Academic Validation
  3. Silybin inhibits succinate production and secretion in hepatocytes to reverse liver fibrosis

Silybin inhibits succinate production and secretion in hepatocytes to reverse liver fibrosis

  • Arch Pharm Res. 2025 Aug;48(7-8):782-797. doi: 10.1007/s12272-025-01560-2.
Xule Yang # 1,  Yunge Lou # 1,  Huan Li 1,  Yuanyuan Ma 1,  Zihan Wang 1,  Jiye Aa 1,  Guangji Wang 2 3,  Yuan Xie 4
Affiliations

Affiliations

  • 1 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. guangjiwang@hotmail.com.
  • 3 Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China. guangjiwang@hotmail.com.
  • 4 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. yuanxie@cpu.edu.cn.
  • # Contributed equally.
PMID: 40739373 DOI: 10.1007/s12272-025-01560-2
Abstract

Silybin has been used as a therapeutic agent in treating liver fibrosis worldwide with unclear mechanisms. In this study, mice were fed a CDAHFD for six weeks to induce liver steatosis and mild liver fibrosis. Metabolomic analysis of mouse liver mitochondria revealed that silybin reversed metabolic abnormalities and diminished succinate accumulation within the mitochondria. Lipidomic profiling revealed marked decreases in mitochondrial membrane Phospholipids (PE, PS, PC, and PI) in CDAHFD-fed mice, along with a substantial reduction in cardiolipin (CL)-a critical component for Succinate Dehydrogenase (SDH) complex assembly. Silybin restored mitochondrial membrane Phospholipids, enhanced CRLS1 expression, facilitated the assembly of SDHA and SDHB, and rejuvenated SDH activity. CRLS1 knockdown via siRNA significantly impaired SDH function, leading to mitochondrial succinate accumulation. Moreover, silybin inhibited succinate efflux by downregulating the expression of the MCT1 transporter. Conditioned medium from palmitic acid/silybin-treated hepatocytes, containing reduced succinate levels, effectively suppressed LX-2 activation. This research indicates that silybin alleviates MASH-induced liver fibrosis by inhibiting succinate generation and its extracellular release, thereby inactivating hepatic stellate cells. These results suggest that targeting succinate production or secretion may represent a promising therapeutic strategy against liver fibrosis progression.

Keywords

CRLS1; Cardiolipin; Liver fibrosis; MASH; SDH; Succinate.

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