Multidimensional immunomodulation by dihydroartemisinin in autoimmune diseases

Autoimmune diseases represent a continuously evolving global health burden driven by immune tolerance breakdown. Current clinical paradigms relying on conventional immunosuppressants primarily offer palliative relief and frequently induce severe systemic toxicities. Consequently, the development of highly efficacious and well-tolerated alternative immunomodulatory therapies constitutes an urgent public health imperative. This comprehensive review systematically synthesizes contemporary basic and preclinical literature regarding the pharmacological evolution of the antimalarial agent dihydroartemisinin into a potent immunomodulator. Dihydroartemisinin profoundly restores systemic immune homeostasis by precisely remodeling adaptive lymphocyte subpopulations. Specifically, the compound restricts pathogenic T helper 1 and T helper 17 cell polarization while expanding immunosuppressive regulatory T cells. Furthermore, dihydroartemisinin mitigates innate immune hyperactivation by driving macrophage metabolic reprogramming from glycolysis toward oxidative phosphorylation. These cellular transformations are orchestrated through complex intracellular signaling networks involving the blockade of nucleic acid sensing pathways and the modulation of kinase cascades. Recent advances in chemical proteomics have further elucidated direct molecular targets, confirming its highly specific intervention mechanisms. By unravelling these multidimensional molecular networks, this work establishes a robust theoretical foundation to accelerate the clinical translation of dihydroartemisinin as a broad-spectrum therapeutic candidate for multisystem autoimmune disorders.