Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting, chronic systemic inflammation, and profound metabolic imbalance. Sustained activation of the nuclear factor κB (NF-κB) signaling pathway lies at the core of its pathogenesis, driving muscle proteolysis, impairing regenerative capacity, disrupting adipose tissue homeostasis, and promoting insulin resistance and anorexia. By transcriptionally regulating catabolic and pro-inflammatory gene programs across skeletal muscle, adipose tissue, the liver, and the central nervous system, NF-κB establishes a self-amplifying inflammatory–metabolic loop that perpetuates tissue wasting and systemic dysfunction. Accumulating preclinical and clinical evidence identifies NF-κB as a viable therapeutic target in cancer cachexia. Pharmacologic inhibitors (e.g., SR12343, DHMEQ), anti-inflammatory strategies (e.g., nonsteroidal anti-inflammatory drugs and IL-6 receptor–targeting antibodies), and nutritional interventions (e.g., omega-3 fatty acids) have shown efficacy in attenuating cachexia-associated inflammation, metabolic dysregulation, and tissue loss. Notably, emerging multimodal approaches integrating NF-κB modulation with metabolic support, chemotherapy, and behavioral interventions demonstrate synergistic benefits. This review integrates current mechanistic insights and therapeutic advances, highlighting NF-κB as a central pathogenic axis and a compelling target for translational intervention in cancer cachexia.

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.

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.