Peroxisomal ABCD1 deficiency in mice drives Th1 bias through 25-HC–LXR signaling in CD4+ T cells

X-linked adrenoleukodystrophy (X-ALD) is driven by ABCD1 dysfunction, causing very-long-chain fatty acid (VLCFA) accumulation and cerebral inflammation, yet the role of T cells in X-ALD remains unclear. Here, we show that Abcd1 -deficient CD4 + T cells exhibit a strong Th1 bias, producing more IFN-γ and less IL-10 under antigen-specific immunization in vivo and Th1-polarizing conditions in vitro . Transcriptional profiling revealed early induction of Ifng and Tbx21 (T-bet) and late repression of Prdm1 (Blimp-1), indicating Blimp-1–dependent derepression of IFN-γ and reduced IL-10. Mechanistically, liver X receptor (LXR) signaling was markedly amplified, evidenced by upregulation of Abca1 , Srebf1 , and the oxysterol 25-hydroxycholesterol (25-HC), driven by increased Ch25h . Pharmacological modulation validated this axis: the LXR antagonist SR9238 restored Blimp-1 and IL-10 while reducing IFN-γ, whereas the LXR agonist T0901317 and exogenous 25-HC recapitulated the Abcd1 -deficient phenotype. Thus, 25-HC–LXR signaling suppresses Blimp-1, enforcing Th1 polarization in Abcd1 -deficient CD4 + T cells. These findings define an immunometabolic link between peroxisomal lipid metabolism and T cell differentiation and highlight the 25-HC–LXR–Blimp-1 axis as a mechanistic link regulating CD4 + T−cell polarization, with potential relevance to X-ALD–associated neuroinflammation.