Ferroptotic stress selectively enhances ACSL4 translation during global translational repression in glioblastoma models.
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BACKGROUND: ACSL4 is a major determinant of ferroptotic susceptibility, but the mechanisms underlying rapid ACSL4 protein accumulation during ferroptotic stress, despite modest transcript changes, remain incompletely understood in glioblastoma. We investigated whether ACSL4 undergoes selective translation during stress-induced global translational repression and examined the regulatory and functional significance of this response. METHODS AND RESULTS: U87-MG was the principal mechanistic model; T98G provided phenotypic validation, GB-SCC026 stem-like cells supported genetic/rescue assessment, and paediatric SF188 cells provided supporting heavy-polysome evidence. Erastin reduced SUnSET-measured puromycin incorporation to approximately 62% of the vehicle-control level while ACSL4 translational efficiency (TE) increased approximately twofold and ACSL4 protein increased to 6.20-fold at 12 h; mRNA changes remained modest (maximum approximately 1.48-fold at 48 h). Among 13,842 transcripts, 412 showed increased TE; ACSL4 ranked 57th overall and first among 47 ferroptosis-related genes. A translation-restricted ACSL4 construct with similar observed basal output attenuated stress-induced TE, heavy-polysome recruitment, protein accumulation, lipid peroxidation and ferroptotic sensitivity. RSL3 reproduced the principal translational phenotype. CONCLUSION: Ferroptotic stress reduces global puromycin incorporation while prioritising ACSL4 translation within a restricted transcript subset. mTORC1-sensitive and METTL3/YTHDF-sensitive inputs contribute without a defined hierarchy. Translation restriction and orthogonal RSL3 validation support a functional contribution of stress-inducible ACSL4 translation beyond constitutive expression. Selective ACSL4 translational engagement therefore contributes to ferroptotic susceptibility in the examined glioblastoma models.