Selective inhibition of ELFN2-containing PP1 hinders autophagy and enhances temozolomide sensitivity in glioblastoma.

Glioblastoma (GBM) frequently develops resistance to temozolomide (TMZ), a process critically mediated by pro-survival autophagy. While phosphatase signaling plays an essential role in regulating autophagic adaptation, the specific molecular drivers that functionally link phosphatase activity to TMZ resistance through autophagy remain poorly understood. We identified ELFN2 as a brain-enriched PP1 regulatory subunit that inhibits dephosphorylation activity, leading to phosphorylation of the splicing factor SRRM1. This triggers widespread alternative splicing, particularly a proautophagic mutually exclusive exon switch in TMBIM6, thereby promoting autophagy and TMZ resistance. Upstream, the transcription factor LRRC4 represses ELFN2, while the lncRNA LINC00470 sequesters LRRC4 in the cytoplasm to antagonize this repression. Preclinically, the HDAC inhibitor Vorinostat targets ELFN2, restores PP1 activity, and synergizes with TMZ to overcome resistance in vitro and in vivo. Our study reveals a novel PP1-centered phospho-splicing circuit governing pro-survival autophagy in GBM and provides a mechanistically grounded, immediately translatable combination therapy to combat TMZ resistance.