Maintenance of Carnitine Homeostasis as a Therapeutic Strategy to Attenuate Cisplatin‐Induced Acute Kidney Injury

Acute kidney injury (AKI) has emerged as a significant global public health concern due to its high morbidity and mortality rates. Cisplatin, a highly effective and widely used chemotherapeutic agent, is often limited in clinical application by its nephrotoxicity, particularly AKI. This study aimed to elucidate the mechanisms underlying cisplatin‐induced nephrotoxicity through multi‐omics approaches and to explore potential therapeutic strategies. Serum‐targeted metabolomics revealed a significant reduction in circulating l ‐carnitine and acylcarnitine levels following cisplatin administration. Renal proteomics showed marked downregulation of carnitine/organic cation transporter 2 (OCTN2), while renal lipid metabolomics demonstrated accumulation of medium‐ and long‐chain fatty acids in the kidney. Furthermore, renal fatty acid oxidation (FAO) activity, as measured by ELISA, was significantly decreased. Given the critical role of OCTN2 in renal l ‐carnitine reabsorption and FAO regulation, we investigated whether l ‐carnitine supplementation could alleviate cisplatin‐induced nephrotoxicity. Our findings indicate that cisplatin significantly suppresses OCTN2 expression, thereby disrupting carnitine homeostasis, impairing mitochondrial FAO, destabilizing mitochondrial dynamics, and ultimately inducing apoptosis. In contrast, l ‐carnitine supplementation restored OCTN2 expression, enhanced FAO, activated the AMPK/PGC‐1α/Sirt3 signaling pathway, and attenuated oxidative stress and apoptosis. In conclusion, l ‐carnitine exhibits significant therapeutic potential against cisplatin‐induced nephrotoxicity by modulating multiple targets related to FAO and mitochondrial dynamics.