Senescence-Related Transcriptomic Analysis and Functional Characterization of ANGPTL4 in Lung Adenocarcinoma

Background: Cellular senescence and the senescence-associated secretory phenotype (SASP) can alter communication between tumor cells and the surrounding microenvironment, but the extracellular mediators involved in this process remain poorly defined in lung adenocarcinoma (LUAD). Methods: Bulk transcriptomic analysis was used to characterize senescence-related transcriptional alterations and construct a prognostic signature. ANGPTL4 expression was evaluated in public datasets and clinical samples. Single-cell RNA-sequencing analysis was then performed to map senescence-associated gene-set scores across LUAD cell populations and to examine the cell–cell communication. ANGPTL4 depletion and overexpression were used to assess its effects on LUAD-cell proliferation, migration, and SA-β-gal positivity, while a subcutaneous xenograft model was used to examine tumor growth in vivo. Conditioned-medium and indirect co-culture experiments were performed to assess the effects of ANGPTL4-overexpressing LUAD cells on THP-1-derived macrophage inflammatory responses, and MCC950 was used to evaluate the contribution of NLRP3-associated signaling. Results: Senescence-related transcriptional alterations in LUAD were enriched in inflammatory and immune-related pathways. ANGPTL4 was included in a five-gene prognostic model and selected for functional investigation because it encodes a secreted protein. We found that ANGPTL4 protein levels were increased in LUAD tissues. Single-cell analysis showed relatively high senescence-associated gene-set scores in macrophage-enriched populations, together with stronger cell–cell communication in the higher-score group. ANGPTL4 depletion reduced LUAD-cell migration and SA-β-gal positivity, while its overexpression had the opposite effects and resulted in larger xenograft tumors. Conditioned medium and indirect co-culture experiments showed that ANGPTL4-overexpressing LUAD cells induced inflammatory changes in THP-1-derived macrophages, accompanied by increased NLRP3-associated markers and IL-1β secretion. These changes were partly attenuated by MCC950. Conclusions: These findings suggest that ANGPTL4 is associated with tumor cell–macrophage crosstalk in LUAD and may correlate with senescence-related transcriptional signatures, while the specific biological role of ANGPTL4 remains to be further characterized.