Inflammation: The Pathological Axis of Cisplatin-Induced Renal Injury

Acute kidney injury (AKI) is a common and serious dose-limiting complication of cisplatin chemotherapy. Cisplatin-induced AKI (CI-AKI) is initiated predominantly in proximal renal tubular epithelial cells (RTECs), where cisplatin enters through organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1). This accumulation drives mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, and the release of damage-associated molecular patterns (DAMPs). These signals activate key innate immune pathways, including Toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signaling and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, leading to a cytokine-driven inflammatory response. Macrophages are major infiltrating immune cells in CI-AKI: early M1 polarization amplifies tubular damage, whereas later M2-like macrophages support inflammation resolution and tissue repair. This review summarizes the mechanistic links between RTEC injury, innate immune activation, and RTEC-macrophage crosstalk, and highlights therapeutic opportunities such as TLR4/NF-κB blockade and modulation of macrophage polarization to reduce nephrotoxicity without compromising anticancer efficacy. Overall, an inflammation-centered view of RTEC-macrophage interactions may guide the development of effective renoprotective adjuncts for cisplatin-based regimens.