Luo Shilu, Yang Ming, Jiang Na, Li Chenrui, Liu Yan, Sun Lin
Department of Nephrology, the Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha, Hunan, 410011, China.
Hunan Key Laboratory of Kidney Disease and Blood Purification, No. 139 Renmin Middle Road, Changsha, Hunan, 410011, China.
Mol Med. 2025 Jun 11;31(1):234. doi: 10.1186/s10020-025-01283-6.
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.
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).
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.
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.
顺铂诱导的肾毒性是一种限制顺铂临床应用的关键不良反应。脂肪酸代谢改变与顺铂诱导的肾毒性发病机制有关，但其确切机制仍不清楚。补骨脂素是一种天然黄酮类化合物，具有抗炎、抗氧化和脂质代谢调节特性，但其通过线粒体β-氧化减轻顺铂诱导的肾毒性的作用尚未得到探索。线粒体融合蛋白2（MFN2）已成为脂肪酸氧化（FAO）和脂质稳态的关键调节因子。然而，其在顺铂诱导的肾毒性中的作用尚未得到充分研究。
将C57/6L小鼠随机分为对照组、二甲基亚砜组、顺铂组和顺铂+补骨脂素组。评估血尿素氮（BUN）、血清肌酐（SCr）、活性氧（ROS）、脂质蓄积和细胞凋亡情况。在体外，将人近端肾小管上皮细胞系（HK-2）细胞用20 μM顺铂处理，同时或不同时添加补骨脂素。用DCFH-DA检测ROS产生，用油红O染色检测脂质沉积，用蛋白质免疫印迹法（WB）检测MFN2、肉碱棕榈酰转移酶1a（CPT1a）。
与顺铂组相比，补骨脂素治疗使顺铂组的BUN（降低21.8%）和SCr（降低78.7%）降低，同时改善了肾脏病理变化、脂质沉积和细胞凋亡。此外，补骨脂素上调了MFN2和CPT1a的表达，同时减少了顺铂诱导的ROS过量产生。在体外也发现了类似结果。值得注意的是，用补骨脂素处理的HK-2细胞中线粒体FAO增加。此外，MFN2小干扰RNA部分逆转了这些保护作用，同时CPT1a表达降低，脂质沉积加剧。
本研究首次证实MFN2是补骨脂素肾脏保护作用的靶点。机制上，补骨脂素通过上调MFN2表达减轻顺铂诱导的脂质蓄积和细胞凋亡，激活CPT1a以促进线粒体FAO。这些结果将为基于顺铂治疗癌症及其降低肾毒性提供新策略。
