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ARL13B is associated with an interferon-STAT1 program in temozolomide-resistant glioblastoma

ABSTRACT: ARL13B, a ciliary GTPase, promotes temozolomide (TMZ) resistance in glioblastoma (GBM) through purine metabolism, but its non-metabolic functions remain unclear. Here we show that high ARL13B expression, based on CGGA database analysis, correlates with poor prognosis in GBM patients. Using transcriptomic profiling, we find that ARL13B is associated with activation of type I interferon and antiviral response pathways, exhibiting an IFN-β-centered signaling state. ARL13B-overexpressing cells show sustained STAT1 activation, with elevated levels of both phosphorylated and total STAT1 protein. STAT1 contributes to these effects, as its inhibition reverses ARL13B-associated TMZ resistance and reduces stemness (SOX2/NANOG expression and sphere formation) in vitro. In vivo, combining TMZ with Fludarabine significantly suppresses tumor growth in ARL13B-overexpressing xenografts compared to monotherapy. These findings suggest a non-metabolic function of ARL13B in promoting a type I interferon-like response leading to sustained activation of the IFN-STAT1 axis, which may contribute to glioma stemness and chemoresistance. This signaling axis could represent a potential therapeutic vulnerability in ARL13B-high, TMZ-resistant GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE335581 | GEO | 2026/09/09

REPOSITORIES: GEO

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