Background: Cellular senescence is a key regulatory mechanism in tumor initiation and progression, influencing cancer development through modulation of the cell cycle, the immune microenvironment, and inflammatory responses. However, the molecular characteristics and potential clinical value of senescence-related genes in lung adenocarcinoma (LUAD) have not been systematically elucidated. This study aimed to comprehensively characterize the expression patterns, molecular subtypes, and prognostic significance of cellular senescence-related genes in LUAD, and to identify key regulatory determinants. Methods: Transcriptomic data of cellular senescence-related genes were obtained from The Cancer Genome Atlas (TCGA) cohort, and integrated analyses were performed to characterize their mutational landscape, copy number variations, and differential expression profiles. Senescence-related molecular subtypes were established using consensus clustering, followed by gene set variation analysis (GSVA) for pathway enrichment and immune infiltration analyses. A prognostic risk model was subsequently constructed using LASSO-penalized Cox regression, and its predictive performance was systematically evaluated. Candidate key regulators were further prioritized through bioinformatic screening, identifying FOLR1 as a hub gene. The biological function of FOLR1 was validated by qRT–PCR, Western blotting, assessment in clinical specimens, and a subcutaneous xenograft tumor model in mice. Results: Cellular senescence-related genes in LUAD exhibited a high frequency of somatic mutations and copy number alterations, accompanied by marked transcriptional dysregulation. Based on the expression profiles of these genes, LUAD patients could be stratified into three distinct molecular subtypes with significantly different clinical outcomes. These subtypes displayed pronounced heterogeneity in pathway enrichment patterns and immune cell infiltration. The subsequently developed prognostic signature demonstrated robust predictive performance in both the training and validation cohorts. Functional assays showed that FOLR1 was significantly downregulated in LUAD tissues and cell lines; FOLR1 knockdown promoted tumor cell proliferation, whereas restoration of its expression or pharmacological intervention markedly suppressed tumor progression. Consistently, in vivo xenograft experiments further corroborated the tumor-suppressive role of FOLR1 in lung adenocarcinoma. Conclusions: This study systematically delineated the molecular landscape of cellular senescence-related genes in LUAD and elucidated their associations with the tumor immune microenvironment and patient prognosis. Moreover, FOLR1 was identified as a potential tumor suppressor and therapeutic target. These findings provide a theoretical basis for senescence-informed molecular stratification and the development of precision treatment strategies in lung adenocarcinoma.

Background: Skeletal muscle wasting is a frequent systemic complication of esophageal cancer and is associated with unfavorable clinical outcomes. However, the relationships among tumor-associated molecular characteristics, patient prognosis, and skeletal muscle alterations remain incompletely understood. This study aimed to identify prognostically relevant genes from a literature-curated muscle wasting-related gene set and investigate the potential association of ZBTB7C with tumor-related skeletal muscle alterations in esophageal squamous cell carcinoma (ESCC). Methods: Transcriptomic and survival data from the complete TCGA-ESCA cohort and the independent GSE53625 cohort were analyzed using a predefined set of genes implicated in muscle wasting-related biology. Differential expression analysis, consensus clustering, Cox regression, LASSO-Cox analysis, survival analysis, functional enrichment, and immune-related analyses were performed. A six-gene prognostic signature was constructed in the TCGA cohort and externally evaluated in GSE53625. ZBTB7C was subsequently investigated using human ESCC tissues and cell lines, Zbtb7c-overexpressing AKR cells, AKR-conditioned medium-treated C2C12 myotubes, and an immunocompetent AKR/C57BL/6 syngeneic tumor model. Results: A total of 32 literature-curated muscle wasting-related genes were retained for analysis. A six-gene prognostic signature comprising ZBTB7C, DDIT3, RNF157, AMOTL1, TTLL12, and PDLIM2 was associated with overall survival, although its discriminatory performance was limited in the external validation cohort. ZBTB7C expression was reduced in ESCC tissues and cell lines, and higher expression was associated with favorable survival. Zbtb7c overexpression reduced PCNA expression in AKR tumor cells. Conditioned medium from Zbtb7c-overexpressing AKR cells attenuated MuRF-1 and Atrogin-1 expression, partially restored AKT, FOXO3A, and P70S6K phosphorylation, and increased global protein synthesis in C2C12 myotubes. In vivo, Zbtb7c overexpression suppressed tumor growth and was accompanied by preservation of gastrocnemius muscle mass, attenuation of muscle protein homeostasis-related alterations, and a smaller decline in all-limb grip strength. Conclusions: These findings identify ZBTB7C as an exploratory candidate associated with esophageal cancer prognosis and tumor-related skeletal muscle alterations. However, its muscle-related effects cannot be fully distinguished from reduced tumor burden, and further mechanistic and clinical validation is required before its potential utility as a biomarker or therapeutic target can be established.

Background: Doxorubicin (DOX) is widely used in breast cancer treatment; however, therapeutic resistance and an immunosuppressive tumor microenvironment remain major obstacles to effective therapy. Immunogenic cell death (ICD) contributes to chemotherapy-induced antitumor immunity, but the molecular regulators linking DOX response, ICD-related signaling, and immune infiltration in breast cancer remain incompletely understood. This study aimed to identify and experimentally validate HSP90AA1 as a potential regulator of DOX response and ICD-associated immune remodeling in breast cancer. Methods: ICD-related genes were analyzed using public breast cancer transcriptomic datasets to construct prognostic models and evaluate their associations with survival, immune infiltration, immune checkpoint expression, and HLA-related molecules. HSP90AA1 was selected as a candidate gene for further validation. HSP90AA1 expression was examined in breast cancer tissues and cell lines. HSP90AA1 knockdown was performed in breast cancer cells, followed by DOX treatment. Western blotting was used to detect apoptosis-related proteins, ICD-related markers, and immune-associated molecules, including cleaved-caspase-3, BAX, BCL-2, CALR, HMGB1, p-eIF2α/eIF2α, and PD-L1. In vivo, a 4T1 syngeneic breast cancer mouse model was established to assess the effects of HSP90AA1 knockdown combined with DOX on tumor growth and tumor immune-related protein expression. Results: Bioinformatic analyses showed that ICD-related molecular patterns were associated with prognosis and immune microenvironment features in breast cancer. HSP90AA1 was upregulated in breast cancer and associated with unfavorable survival, supporting its potential relevance as an ICD-related prognostic candidate. In vitro, HSP90AA1 knockdown enhanced DOX-induced apoptotic responses, as indicated by increased cleaved-caspase-3 and BAX expression and decreased BCL-2 expression. HSP90AA1 knockdown also strengthened DOX-induced ICD-related molecular changes, including increased CALR, HMGB1, and p-eIF2α/eIF2α levels, accompanied by altered PD-L1 expression. In vivo, Hsp90aa1 knockdown combined with DOX resulted in a greater reduction in terminal tumor burden than DOX treatment alone. Tumor tissues from the combination group showed increased CALR, HMGB1, CD8A, and GZMB expression, together with altered PD-L1 expression. Tumor tissues from the combination group showed increased CALR, HMGB1, CD8A, and GZMB expression, together with altered PD-L1 expression, indicating ICD-related and immune-associated molecular changes. Conclusions: This study identifies HSP90AA1 as a potential ICD-related regulator of DOX response in breast cancer. HSP90AA1 knockdown may enhance the response to DOX by promoting apoptotic responses and ICD-related molecular changes, together with immune-related tumor microenvironment remodeling. These findings provide experimental evidence supporting HSP90AA1 as a potential therapeutic target for improving chemotherapy response in breast cancer.