controls were subjected to cisplatin-induced AKI. Untargeted metabolomics of kidney cortex and single-nucleus RNA sequencing (snRNA-seq) were performed to define metabolic and cell-specific transcriptional responses. Loss of proximal tubular LDHA exacerbated cisplatin-induced AKI, as evidenced by worsened kidney function and tubular injury, accompanied by increased expression of inflammatory markers following injury. The analysis also showed a distinct metabolic profile at baseline in LDHA-deficient kidneys, which became more pronounced after cisplatin exposure, with coordinated changes in purine and nucleotide metabolism, energy-related metabolites, and pathways linked to redox balance and mitochondrial function. snRNA-seq revealed intrinsic transcriptional changes within proximal tubule cells at baseline and after injury, reflecting cellular stress and metabolic remodeling without strong activation of classic inflammatory gene programs. Together, these findings identify proximal tubular LDHA as a key regulator of metabolic flexibility and injury tolerance in cisplatin-induced AKI, and suggest that disrupted coordination of glycolytic and nucleotide metabolism increases tubular vulnerability, highlighting metabolic regulation as a potential therapeutic target.
Lu et al. (Wed,) studied this question.