Proteotoxicity and tubular epithelial cell fate in acute kidney injury: Molecular insights and treatment strategies.

Acute kidney injury (AKI) is the most frequent renal complication, characterized by a rapid and severe loss of kidney function. Given its high incidence and strong propensity to progress into chronic kidney disease (CKD), a deeper insight into its molecular pathology is critical for the development of more effective therapies. In this review, we offer a novel conceptual framework illustrating how diverse AKI triggers induce oxidative stress-driven protein damage, which can exceed the capacity of endogenous protein quality control systems, ultimately promoting proteotoxic stress and renal tubular epithelial cells (RTECs) demise. Importantly, we emphasize the central role of proteotoxicity in shaping the core features of unresolved AKI such as tubular cast formation, impaired proliferation and differentiation of surviving RTECs, mitochondrial and metabolic dysfunction in RTECs. Through this discussion on the relevance of proteotoxicity to the major molecular mechanisms underlying AKI, we highlight its central role in regulating renal tubular epithelial cell fate-balancing survival and death under AKI conditions-and propose that sustained proteotoxic stress may serve as a critical link driving the transition from AKI to CKD. We further outline experimental approaches to identify RTEC proteins susceptible to aggregation during AKI and discussed emerging therapeutic strategies aimed at enhancing their clearance. By delineating key mechanisms linking RTEC proteotoxic stress to cell survival and repair, we aim to spotlight this underexplored dimension of AKI biology, inspiring future research and therapeutic innovation to alleviate AKI burden and hinder AKI-to-CKD progression.