From Single-target to System Remodeling：Combination Therapeutic Strategies for Metabolic Diseases

Metabolic diseases are characterized by complex pathological features involving multi-organ dysfunction and multi-pathway dysregulation. Therapeutic strategies targeting a single biomarker or pathway have shown limited effectiveness in halting disease progression. Taking type 2 diabetes mellitus （T2DM） as an example，the coexistence of hyperglycemia，insulin resistance，lipid metabolism disorders，and chronic inflammation leads to simultaneous damage across key systems such as the β-cell，liver，heart，and kidneys. However，current treatments primarily focus on glycemic control and lack systemic interventions that address multi-organ pathologies，resulting in persistently high rates of complications. Against this backdrop，a paradigm shift is underway—from reductionist，single-target approaches to integrated，systems-level therapeutic strategies. Combination drug development lies at the heart of this strategic transition，aiming to reconstruct pathological networks through coordinated，multi-target，multi-pathway interventions that enhance efficacy while minimizing toxicity. This article reviews recent advances and emerging directions in combination therapy for metabolic diseases such as metabolic dysfunction-associated steatohepatitis （MASH），type 2 diabetes，and cardiovascular disease. The discussion provides forward-looking insights to inform global strategies for the prevention and management of metabolic disorders.