Autophagy in myositis, a dysregulated pathway, and a target for therapy

Abstract

Corticosteroids and immunosuppressants are the mainstay of therapy for idiopathic inflammatory myopathies (IIMs). However, a significant therapeutic challenge extends beyond mitigating inflammation with these agents in achieving meaningful improvements in muscle strength and physical function, a goal that remains largely unmet. IIMs encompass a heterogeneous group of autoimmune disorders, including dermatomyositis, polymyositis, necrotizing autoimmune myopathy, inclusion body myositis, and others, characterized by chronic muscle inflammation, progressive weakness, and fatigue. The etiology of IIMs remains poorly understood, though potential contributors include environmental triggers (e.g., infections, medications, or injury) and genetic predisposition. To advance the development of novel therapeutic strategies, it is critical to elucidate the dysfunctional molecular and cellular pathways underlying IIM pathogenesis. Among these, dysregulated autophagy pathways have emerged as a promising target for therapeutic intervention. Specifically, impairments in lysosomal autophagy and mitophagy have been implicated in IIMs, and modulating these processes through targeted regulatory mechanisms may offer therapeutic benefits. This review provides a comprehensive synthesis of clinical and biological features of IIMs, the current diagnostic approaches and emerging biomarkers, evaluates the utility of existing biomarkers, and examines the relevance of animal models in IIM research. Furthermore, we explore the role of autophagic dysregulation in disease pathogenesis and provide a critical appraisal of current treatment modalities. Finally, we highlight emerging therapeutic targets and regulatory molecules under investigation, with a particular focus on autophagy modulation. Notably, autophagy inhibitors represent a novel and potentially transformative therapeutic avenue for patients with IIMs, offering hope for improved clinical outcomes.