Targeting the SARM1-NAD⁺ axis: A review of new strategy for reversing the imbalance of energy and mitochondrial homeostasis in metabolic diseases

Metabolic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), diabetes, and their multi-organ complications, are characterized by high prevalence, systemic involvement, and a lack of effective reversal strategies. Their pathological core involves energy metabolism imbalance, chronic inflammation, and multi-tissue injury. In recent years, Sterile Alpha and TIR Motif Containing 1 (SARM1), an NAD⁺ hydrolyzing signaling molecule, has been repositioned from a single executor of axonal degeneration to a cross system metabolic regulatory node. By depleting NAD⁺, disrupting mitochondrial homeostasis, and modulating neuroimmune signaling, SARM1 predominantly exerts pro-injury effects in obesity, NAFLD, cardiac disorders, and peripheral neuropathies. However, in specific cell types, such as hepatic stellate cells, its interaction dependent activity can suppress fibrosis, revealing a striking context dependent duality. Despite these findings, a systematic understanding of SARM1's cell-type-specific regulation, tissue heterogeneity and long-term intervention safety in metabolic diseases remains limited, thereby constraining its translational potential. This review outlines the structural characteristics and activation mechanisms of SARM1 and, for the first time, discusses its context-dependent roles in metabolic diseases. It also summarizes emerging pharmacological intervention strategies, including small-molecule inhibitors, natural product modulators, and agonists, aiming to provide a theoretical basis for precise interventions in metabolic diseases and to inspire novel therapeutic approaches.