Deciphering gentamicin-induced nephrotoxicity and hepatotoxicity: Pathophysiological insights and emerging protective approaches.

Gentamicin (GEN) is a critical aminoglycoside antibiotic for severe gram-negative infections, yet its clinical utility is limited by dose-dependent nephrotoxicity (occurring in 10-25% of therapeutic courses) and hepatotoxicity. Nephrotoxicity arises from GEN accumulation in proximal tubular cells, triggering reactive oxygen species overproduction, lipid peroxidation, mitochondrial dysfunction, and intrinsic apoptotic pathway activation. Hepatotoxicity involves analogous oxidative and inflammatory mechanisms compromising hepatocellular integrity. At the molecular level, GEN-induced injury involves interconnected pathways: oxidative stress drives lipid peroxidation and depletes endogenous antioxidants; TLR4/NF-κB signaling amplifies pro-inflammatory cytokines (TNF-α, IL-1β, IL-6); NLRP3 inflammasome activation potentiates pyroptosis; the cytoprotective Nrf2/HO-1 pathway is suppressed; and Bax/Bcl-2/caspase-3 mediates terminal apoptotic death. This review systematically consolidates evidence on GEN's pharmacological profile, pathophysiological mechanisms of both organ toxicities, predisposing risk factors, and protective agents demonstrating preclinical efficacy. Nephroprotective and hepatoprotective compounds including polyphenols, flavonoids, alkaloids, and synthetic pharmacological agents are comprehensively summarized. Understanding these protective mechanisms may inform rational co-administration strategies; all supporting evidence is, however, preclinical, and none of these agents has yet been evaluated for the prevention of GEN-induced organ injury in patients, as illustrated through a proposed multi-target hepatorenoprotective framework. The proposed multi-target hepato-reno-protective strategy during GEN therapy is illustrated in Fig. 1.