Protective Role of Linagliptin in Cisplatin‐Mediated Liver Injury: Involvement of STAT3 and AMPK/SIRT1/PGC‐1alpha Mitochondrial Energy Sensing Networks

Abstract

Cisplatin (Cis), a commonly used chemotherapy drug, is associated with liver toxicity, which restricts its broader clinical use. This study investigated the potential protective effects of linagliptin (Lina), a DPP‐4 inhibitor, in preventing liver damage induced by Cis in rats. There were four groups of male rats: a control group, a Cis group (8 mg/kg, IP), and cotreated groups given Lina (5 and 10 mg/kg, orally) with Cis. Lina was administered daily for 15 days, with Cis injected on Day 8. Liver function, oxidative stress markers, inflammatory mediators, energy metabolism indicators, and key signaling proteins were assessed. Cis administration resulted in significant hepatotoxicity, evidenced by elevated liver enzymes, increased oxidative stress, enhanced inflammatory response, and disrupted energy metabolism. Lina treatment, particularly at the 10‐mg/kg dose, demonstrated marked hepatoprotective effects. It significantly reduced liver enzyme levels, improved antioxidant status, attenuated inflammatory markers, and restored energy metabolism indicators. Moreover, Lina positively modulated essential signaling proteins involved in cellular stress response and metabolism, including signal transducer and activator of transcription 3 (STAT3), transforming growth factor beta 1 (TGF‐β), silent information regulator 1 (SIRT1), and peroxisome proliferator–activated receptor gamma coactivator 1‐alpha (PGC‐1α). The results indicate that Lina protects against Cis‐induced liver damage by leveraging its antioxidant, anti‐inflammatory, and metabolic regulation properties. This study offers new insights into potential strategies for mitigating Cis‐induced hepatotoxicity and enhancing its therapeutic index in cancer treatment.