Oxidative Damage as a Fundament of Systemic Toxicities Induced by Cisplatin—The Crucial Limitation or Potential Therapeutic Target?

**Background:** Cisplatin is a widely used chemotherapeutic agent, but its clinical utility is limited by severe systemic toxicities, particularly nephrotoxicity (occurring in 20–41% of patients), peripheral neurotoxicity (up to 86% in adults), and ototoxicity (over 50% in children). The paper posits that oxidative stress is a fundamental mechanism driving these toxicities. Free radicals, especially reactive oxygen species (ROS), are generated through cisplatin's interaction with cellular components, leading to mitochondrial dysfunction, depletion of antioxidants like glutathione (GSH), and activation of inflammatory pathways. The review aims to synthesize current knowledge on cisplatin-induced oxidative damage and explore potential therapeutic targets to mitigate these effects.

**Methods:** This is a narrative review that synthesizes published literature on cisplatin-induced oxidative stress and its role in systemic toxicities. It covers mechanisms of cisplatin action, oxidative damage pathways, and recent animal model studies. The review includes a table summarizing 22 recent in vivo studies (2019–2023) that investigated various interventions (e.g., aspirin, nanoparticles, natural compounds) in rodent and zebrafish models to ameliorate cisplatin-induced toxicities. The studies assessed endpoints such as oxidative stress markers (e.g., ROS, MDA, GSH), inflammatory cytokines (e.g., TNF-α, IL-1β), apoptosis markers, and histopathological changes.

**Key Results:** The review identifies that cisplatin-induced oxidative stress arises from multiple mechanisms: (1) direct binding to GSH, reducing antioxidant capacity; (2) mitochondrial dysfunction, leading to increased ROS production; (3) activation of signaling pathways (e.g., MAPK, p53, NF-κB) that promote inflammation and apoptosis. In animal models, interventions such as aspirin (5–40 mg/kg), 7-hydroxycoumarin-β-D-glucuronide (7.5–30 mg/kg), and fucoidan-proanthocyanidins nanoparticles (50–100 mg/kg) reduced nephrotoxicity by lowering oxidative stress and inflammation. For neurotoxicity, lansoprazole (50 mg/kg) and Hypericum nanoemulsion (100 mg/kg) improved behavioral outcomes and reduced oxidative parameters. Ototoxicity studies in mice and zebrafish showed that PRMT5 inhibitors and esomeprazole (2–200 μM) protected hair cells via mitochondrial pathways. The review emphasizes that oxidative stress reduction is a common endpoint across all studies, with many interventions activating Nrf2 signaling or inhibiting NF-κB.

**Clinical Implications:** The review underscores that oxidative stress is a critical therapeutic target for mitigating cisplatin-induced toxicities. It suggests that antioxidant-based cotreatments, including natural compounds (e.g., flavonoids, terpenoids) and synthetic agents (e.g., thiol protectors), could be used adjunctively to reduce side effects without interfering with cisplatin's anticancer activity. However, the review cautions that many animal studies focus on single toxicities and may not fully capture the interplay between organ systems. It highlights the need for rigorous, well-designed clinical trials to validate these strategies. The development of nanoparticle-based delivery systems (e.g., ROS-responsive nanoparticles) offers promise for targeted antioxidant therapy. The review also notes that cisplatin resistance remains a major limitation, and future research should explore combination therapies that simultaneously reduce toxicity and overcome resistance.