Research Progress on the Treatment of Renal Injury with Esculetin: Multi-Target Pharmacological Mechanism and Clinical Translation Prospect

Kidney injury is a major clinical syndrome that can arise from nephrotoxins, ischemia–reperfusion, metabolic disease, infection, and immune dysregulation and can progress from acute kidney injury (AKI) to chronic kidney disease (CKD). Esculetin, a natural 6,7-dihydroxycoumarin derived from Cortex Fraxini, has antioxidant, anti-inflammatory, mitochondrial regulatory, anti-apoptotic, anti-ferroptotic, and anti-fibrotic activities. Preclinical studies report renoprotection in cisplatin-induced AKI, diabetes complicated by ischemia–reperfusion-induced AKI, and adenine-induced chronic renal injury, with changes in Nrf2/HO-1, NF-kappaB/MAPK, PINK1/Parkin-associated mitophagy, endoplasmic reticulum stress, regulated cell death, and fibrotic signaling. However, the evidence is based on a small number of heterogeneous cell and rodent studies, direct molecular targets remain uncertain, and no human studies have validated efficacy, dosing, or safety. Low oral bioavailability, rapid conjugative metabolism, limited long-term toxicology, and the absence of pharmacokinetic–pharmacodynamic relationships are major barriers to translation. This review critically synthesizes the renal evidence for esculetin and identifies the experimental, pharmaceutical, and clinical studies required to determine whether it can progress from a promising multi-target natural product to a renoprotective therapeutic candidate.