Pharmacovigilance assessment of drug-induced hypokalemia: from systemic risk screening to multi-dataset bioinformatics analysis focused on cisplatin.

Drug-induced hypokalemia is a common yet clinically insidious electrolyte disorder, but systematic evaluations of the risk profile of associated medications remain limited. This study was aimed at identifying high-risk drugs for hypokalemia via signal mining of the FAERS database, combined with bioinformatics analysis, clinical validation, and in vitro experiments, thereby elucidating the molecular basis of this condition and providing evidence for clinical risk management. Adverse event reports from 2004 Q1 to 2024 Q4 were analyzed using four disproportionality methods (ROR, PRR, BCPNN, and MGPS), integrated with multivariate logistic regression to assess drug-hypokalemia associations and risk factors. For cisplatin, the core high-risk drug identified, potassium metabolism-related differentially expressed genes were screened from the GEO dataset GSE145085. Candidate gene mRNA expression was validated by qPCR in 293 T and HK-2 cells. STRING protein-protein interaction (PPI) network analysis was performed to explore the link between candidate genes and potassium homeostasis. Additionally, ClinicalTrials.gov data were retrieved to confirm the clinical relevance of cisplatin-induced hypokalemia. FAERS analysis identified a total of 24,041 reports related to hypokalemia. The study identified 1199 suspected drugs, with 22 high-risk medications showing a significant association with hypokalemia, including cisplatin. In vitro experiments demonstrated that treatment with cisplatin for 24 h significantly altered the mRNA expression of GDF15, KCNQ1, and CLCNKB in 293 T and HK-2 cells, consistent with bioinformatics findings. STRING PPI analysis further revealed that GDF15 interacts with core components of the TGF-β/SMAD signaling pathway, while KCNQ1 and CLCNKB interact with critical regulators of renal potassium and chloride transport, collectively establishing a plausible molecular framework linking these genes to cisplatin-induced potassium homeostasis dysfunction. This study systematically identified 22 high-risk drugs associated with hypokalemia, including cisplatin. Bioinformatics analysis and in vitro experiments were further conducted to investigate the potential mechanisms underlying cisplatin-induced hypokalemia. The findings provide novel insights into the molecular basis of drug-induced hypokalemia and offer scientific support for promoting individualized rational medication and clinical management in affected patients.