Cathepsins as Core Players in Obesity Pathogenesis: Emerging Therapeutic Targets.

Obesity is a chronic metabolic disorder associated with multiple serious complications and has become a major global public health problem. Accumulating evidence indicates that members of the cathepsin (Cath) family play an important role in the development of obesity pathogenesis, thereby emerging as promising therapeutic targets for intervention. This study summarizes the multiple regulatory mechanisms of Caths involved in obesity and discusses their regulation of adipocyte differentiation, cell death, metabolism, and adipose tissue inflammation. Building on these mechanisms, we further elaborate on three novel strategies targeting Caths for obesity intervention, including selective small-molecule inhibitor development, targeted delivery systems via nanocarriers, and gene modulation approaches targeting specific Cath subtypes. Despite robust preclinical data demonstrating the efficacy of Cath-targeted interventions in ameliorating obesity and associated metabolic disorders, several critical challenges impede their clinical translation, notably: functional redundancy among Cath family members, off-target effects and unpredictable long-term safety profiles, limited subtype selectivity of existing inhibitors and immunogenicity risks associated with nanodelivery systems. To promote strategies for the clinical translation of Cath-targeted anti-obesity therapies, future research priorities should encompass artificial intelligence (AI)-driven high-throughput screening and rational design of highly selective Cath inhibitors, validation of specific Cath subtypes as clinically actionable diagnostic and prognostic biomarkers for obesity and metabolic risk stratification, and the development of personalized precision medicine strategies tailored to individual metabolic phenotypes and Cath expression profiles.