What does this research mean for the field?

ACOD1 deficiency drives dermal papilla cell senescence and hair loss in androgenetic alopecia by promoting DDX1 methylation and mitochondrial dysfunction, a process that can be mitigated by 4-octyl itaconate supplementation. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to elucidate the molecular mechanisms by which ACOD1 deficiency contributes to dermal papilla cell senescence and mitochondrial dysfunction in androgenetic alopecia.

June 1, 2026Open Access

ACOD1 deficiency promotes DDX1 methylation–mediated mitochondrial dysfunction and dermal papilla cell senescence in androgenetic alopecia

Key Points

This research aims to elucidate the molecular mechanisms by which ACOD1 deficiency contributes to dermal papilla cell senescence and mitochondrial dysfunction in androgenetic alopecia.
Utilized human scalp tissues and DHT-induced AGA mouse models to investigate DPC senescence and mitochondrial dysfunction.
Performed RNA sequencing and metabolomic analysis to identify alterations in gene expression and metabolic profiles.
Conducted functional experiments involving ACOD1 knockdown/overexpression and treatment with 4-octyl itaconate (4-OI) to assess impacts on mitochondrial function and cell behavior.
ACOD1 knockdown in DPCs led to increased senescence markers and mitochondrial dysfunction, with significant reductions in cell proliferation and migration.
4-OI treatment in AGA mice reduced DDX1 methylation and improved mitochondrial function, enhancing cell proliferation while decreasing hair loss symptoms.
RNA sequencing revealed ACOD1 downregulation in DHT-treated DPCs, with its overexpression counteracting DHT-induced age-related cellular changes.

Abstract

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. 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 (p16INK4a, 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 ACOD1 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. 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 ACOD1 as significantly downregulated in DHT-treated DPCs. ACOD1 knockdown induced mitochondrial dysfunction, cellular senescence, and functional impairment in DPCs, while ACOD1 overexpression ameliorated these DHT-induced phenotypes. Mechanistically, ACOD1 interacted with DDX1 to inhibit its methylation; ACOD1 knockdown enhanced DDX1 methylation, correlating with mitochondrial dysfunction and DPC senescence. Metabolomic analysis demonstrated that ACOD1 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. Our findings reveal a novel mechanism underlying DPC senescence in AGA, wherein ACOD1 deficiency promotes DDX1 methylation, mitochondrial dysfunction, and subsequent DPC senescence. ACOD1 represents a promising therapeutic target for AGA, and 4-OI may have translational potential for the treatment of AGA.

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