HSPB1 promotes gastric cancer progression by suppressing PANoptosis

Abstract

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, driven by molecular mechanisms that promote tumor progression and therapeutic resistance. PANoptosis, an integrated programmed cell death pathway involving apoptosis, necroptosis, and pyroptosis, has emerged as a key regulator of tumorigenesis, yet its modulation in GC is poorly understood. This study aimed to investigate the role of heat shock protein beta-1 (HSPB1) in regulating PANoptosis and its impact on GC progression, hypothesizing that HSPB1 overexpression suppresses PANoptosis to enhance tumor malignancy. We employed an integrative approach combining bioinformatics analysis of GEO (GSE54129), TCGA, and GSE15460 datasets with experimental validations. HSPB1 expression was assessed in 40 paired GC and normal tissues and multiple GC cell lines (AGS, MKN-45, NCI-N87, HGC-27, SNU-1) via qPCR, Western blot, and immunohistochemistry. Functional roles were explored by overexpressing or silencing HSPB1 in NCI-N87 and AGS cells, followed by proliferation, colony formation, migration, and apoptosis assays. In vivo effects were evaluated using a nude mouse xenograft model with shHSPB1-transfected cells, analyzing tumor growth and PANoptosis markers (P-MLKL, RIPK3, Cleaved Caspase-1, NLRP3, Cleaved Caspase-3) via Western blot, IHC, and TUNEL assays. Bioinformatics revealed HSPB1 as a PANoptosis-related prognostic biomarker, with elevated expression in GC tissues correlating with poor survival. Experimental validation confirmed HSPB1 overexpression in GC tissues and cell lines. HSPB1 overexpression enhanced proliferation, invasion, and migration while suppressing apoptosis by downregulating PANoptosis markers. Conversely, HSPB1 silencing inhibited these oncogenic traits and activated PANoptosis, significantly reducing tumor growth in vivo, accompanied by upregulated PANoptosis-related proteins and increased apoptosis.HSPB1 promotes GC progression by inhibiting PANoptosis, thereby enhancing tumor survival and aggressiveness, whereas its silencing activates these cell death pathways to suppress tumorigenesis. These findings establish HSPB1 as a critical regulator of PANoptosis in GC and a potential therapeutic target, offering new avenues for overcoming resistance and improving patient outcomes.