MARY1 restores mitochondrial homeostasis and accelerates renal recovery following acute kidney injury.

Acute kidney injury (AKI) is a major clinical concern with limited therapeutic strategies, often leading to chronic kidney disease (CKD) and long-term morbidity. Mitochondrial dysfunction is a major causative factor for AKI onset and progression to CKD. Interventions that restore mitochondrial integrity and cellular energy represent promising therapeutic strategies. This study investigated the potential therapeutic role of MARY1, a novel, potent, and subtype-selective serotonin-2B receptor (5-HT(2B)R) antagonist, following ischemia/reperfusion (I/R)-induced AKI in mice and rats. We previously demonstrated that MARY1 induces renal mitochondrial biogenesis (MB), the generation of new functional mitochondria, in vivo. MARY1 (0.3 mg/kg, i.p., daily) administration for 6 days following AKI improves renal function, restores mitochondrial homeostasis and renal vascular integrity, upregulates β-oxidation, and restores genes associated with proximal tubule repair. Moreover, daily treatment with MARY1 for 12 days following AKI restores mitochondrial homeostasis and increases autophagic activity in the renal cortex of mice. These findings establish MARY1-mediated 5-HT(2B)R antagonism as a mitochondria-targeted therapeutic strategy that addresses multiple hallmarks of AKI, and as a potential intervention for mitochondrial dysfunction-associated renal diseases.NEW & NOTEWORTHY This study identifies MARY1, a subtype selective 5-HT(2B) receptor antagonist, as a novel mitochondria-targeted therapeutic for AKI. MARY1 restores mitochondrial homeostasis, enhances renal vascular integrity, and promotes autophagy and β-oxidation following bilateral I/R injury-induced AKI, leading to improved renal recovery in vivo. These findings highlight a novel therapeutic strategy to mitigate AKI progression and mitochondrial dysfunction.