Mrpl50 integrates glucolipotoxicity with HIF-1α signaling to drive diabetic kidney disease.

Diabetic kidney disease (DKD), a systemic metabolic disorder, leads to renal failure and increased cardiovascular risk. A central driver of its progression is glucolipotoxicity, which triggers renal tubular injury through mechanisms that remain incompletely defined. Here, we identify Mrpl50 as a critical mediator of glucolipotoxic damage. Mrpl50 expression is upregulated under metabolic stress and correlates with DKD progression. Mrpl50 deficiency in renal tubular cell attenuated glucolipotoxic damage, while its overexpression amplified inflammatory responses. Mechanistically, Mrpl50 drives renal inflammation via the HIF-1α pathway. These findings establish Mrpl50 as a molecular sensor that discriminates true hypoxia from metabolically induced pseudo-hypoxia, thereby fine-tuning the HIF-1α response to govern disease progression in DKD.