Background <p>Androgenetic alopecia (AGA), the most prevalent form of hair loss, is driven by the dysfunction of dermal papilla cells (DPCs). Emerging evidence implicates DPC senescence in the pathogenesis of AGA; however, the underlying molecular mechanisms remain incompletely elucidated.</p> Methods <p>We employed a multi-faceted experimental approach, including analyses of human scalp tissues, primary DPCs, a dihydrotestosterone (DHT)-induced AGA mouse model, and immortalized DPCs stimulated with DHT. Cellular senescence was evaluated via expression of senescence markers (p16^INK4a, p21, p53) and senescence-associated β-galactosidase staining. Cell proliferation, migration, and apoptosis were also assessed. Mitochondrial function was evaluated using transmission electron microscopy, MitoTracker, MitoSOX, JC-1, and Seahorse assays. RNA sequencing and bioinformatics analyses were performed to identify differentially expressed genes. The interaction between Aconitate Decarboxylase 1 (ACOD1) and DDX1 was verified via co-immunoprecipitation, mass spectrometry, and molecular docking. Metabolomic analysis was performed to profile intracellular metabolic alterations. Functional experiments included <i>ACOD1</i> knockdown/overexpression and exogenous supplementation with 4-octyl itaconate (4-OI). Hair follicle morphology and hair loss in AGA mice were evaluated following 4-OI treatment.</p> Results <p>Senescence markers were significantly elevated in AGA DPCs, accompanied by increased senescence-associated β-galactosidase staining, reduced cell proliferation and migration, and enhanced apoptosis. DHT-induced mitochondrial dysfunction in DPCs was characterized by increased mitochondrial fragmentation, decreased mitochondrial cristae, superoxide accumulation, reduced membrane potential, and impaired oxidative phosphorylation. RNA sequencing identified <i>ACOD1</i> as significantly downregulated in DHT-treated DPCs. <i>ACOD1</i> knockdown induced mitochondrial dysfunction, cellular senescence, and functional impairment in DPCs, while <i>ACOD1</i> overexpression ameliorated these DHT-induced phenotypes. Mechanistically, ACOD1 interacted with DDX1 to inhibit its methylation; <i>ACOD1</i> knockdown enhanced DDX1 methylation, correlating with mitochondrial dysfunction and DPC senescence. Metabolomic analysis demonstrated that <i>ACOD1</i> knockdown significantly reduced itaconate levels. Exogenous 4-OI supplementation reduced DDX1 methylation, ameliorated DHT-induced mitochondrial dysfunction and cellular senescence, promoted cell proliferation and migration, suppressed apoptosis, mitigated hair follicle miniaturization, and alleviated hair loss in AGA mice.</p> Conclusions <p>Our findings reveal a novel mechanism underlying DPC senescence in AGA, wherein <i>ACOD1</i> deficiency promotes DDX1 methylation, mitochondrial dysfunction, and subsequent DPC senescence. <i>ACOD1</i> represents a promising therapeutic target for AGA, and 4-OI may have translational potential for the treatment of AGA.</p>