GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE317nnn/GSE317900/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE317900GEOGSEfalseZDHHC8-mediated β-catenin palmitoylation promotes WNT signaling activation and drives cisplatin resistance in osteosarcomaChemoresistance remains a major challenge in osteosarcoma therapy, severely limiting the efficacy of cisplatin-based chemotherapy. Here, we identify the palmitoyltransferase ZDHHC8 as a critical determinant of cisplatin resistance and uncover a lipid modification–dependent mechanism that stabilizes β-catenin and sustains WNT signaling. ZDHHC8 expression was markedly upregulated in chemoresistant osteosarcoma tissues, and its knockdown significantly enhanced cisplatin-induced apoptosis both in vitro and in vivo. Transcriptomic profiling and functional assays revealed that ZDHHC8 depletion suppressed WNT/β-catenin signaling and diminished cancer stem cell–like properties. Mechanistically, ZDHHC8 directly interacted with β-catenin and catalyzed its C381-specific palmitoylation, which prevented proteasomal degradation and maintained protein stability. Mutation of C381 abolished β-catenin palmitoylation, resulting in reduced WNT activity and impaired stemness maintenance. Conversely, ZDHHC8 overexpression stabilized β-catenin and conferred cisplatin resistance. Collectively, our findings reveal a previously unrecognized ZDHHC8–β-catenin palmitoylation axis that governs WNT pathway activation and osteosarcoma chemoresistance. Targeting ZDHHC8 or disrupting β-catenin palmitoylation offers a promising therapeutic strategy to overcome drug resistance and improve osteosarcoma outcomes.2026/07/01GSE317900GSM9481401GSM9481402GSM9481397GSM9481398GSM9481399GSM9481400GSM9481395GSM948139616791317900Homo sapiens