Bavachin ameliorates cisplatin-induced nephrotoxicity by enhancing mitochondrial β-oxidation and lipid metabolism through MFN2

  • Mol Med. 2025 Jun 11;31(1):234. doi: 10.1186/s10020-025-01283-6.
Shilu Luo  1  2 ,  Ming Yang  1  2 ,  Na Jiang  1  2 ,  Chenrui Li  1  2 ,  Yan Liu  1  2 ,  Lin Sun  3  4
Affiliations
  • 1. Department of Nephrology, the Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha, Hunan, 410011, China.
  • 2. Hunan Key Laboratory of Kidney Disease and Blood Purification, No. 139 Renmin Middle Road, Changsha, Hunan, 410011, China.
  • 3. Department of Nephrology, the Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha, Hunan, 410011, China. [email protected].
  • 4. Hunan Key Laboratory of Kidney Disease and Blood Purification, No. 139 Renmin Middle Road, Changsha, Hunan, 410011, China. [email protected].
PMID: 40500698 DOI: 10.1186/s10020-025-01283-6
Abstract

Background: Cisplatin-induced nephrotoxicity is a critical adverse reaction that restricts the clinical utilization of cisplatin. Alterations in fatty acid metabolism have been associated with the pathogenesis of cisplatin-induced nephrotoxicity, yet the precise mechanisms remain unclear. Bavachin, a natural flavonoid, exhibits anti-inflammatory, antioxidant, and lipid metabolism-regulating properties, yet its role in mitigating cisplatin-induced nephrotoxicity via mitochondrial β-oxidation remains unexplored. Mitofusin-2 (MFN2), a mitochondrial fusion protein, has emerged as a critical regulator of fatty acid oxidation (FAO) and lipid homeostasis. However, its role in cisplatin-induced nephrotoxicity has not been fully explored.

Methods: C57/6L mice were randomly divided into control, DMSO, cisplatin, and cisplatin + Bavachin groups. Blood urea nitrogen (BUN), serum creatinine (SCr), reactive-oxygen-species (ROS), lipid accumulation, and Apoptosis were assessed. In vitro, the human proximal tubule epithelial cell line (HK-2) cells were treated with 20 µM cisplatin with or without bavachin. ROS production was detected by the DCFH-DA, lipid deposition was detected by oil red O staining, and MFN2, carnitine palmitoyltransferase 1a (CPT1a) were detected by Western blot (WB).

Results: Compared with the cisplatin group, bavachin treatment reduced BUN (21.8%) and SCr (78.7%) in the cisplatin group, accompanied by improvements in renal pathological changes, lipid deposition, and Apoptosis. In addition, bavachin up-regulated the expression of MFN2 and CPT1a, while decreasing the cisplatin-induced ROS overproduction. Similar results were found in vitro. Notably, the mitochondrial FAO has been increased in HK-2 cells treated with bavachin. Further, MFN2 siRNA partially reversed these protective effects, accompanied by decreased CPT1a expression and exacerbated lipid deposition.

Conclusions: This study is the first to confirm MFN2 as a target for renal protection by bavachin. Mechanistically, Bavachin alleviated cisplatin-induced lipid accumulation and Apoptosis by upregulating MFN2 expression, which activated CPT1a to promote mitochondrial FAO. These results will provide a new strategy for cisplatin-based Cancer therapy and the reduction of its nephrotoxicity.

Keywords
Acute kidney injury; Bavachin; Lipid accumulation; MFN2; Mitochondrial dynamics; Oxidative stress; Renal protection.
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