PPARG has been reported to promote chemosensitivity in hypopharyngeal squamous cell carcinoma (HSCC). However, few studies tested its significance in the texture of a complex molecular network regulating chemosensitivity in HSCC. Here, we first employed RNA expression data analysis and literature data mining to uncover candidate genes related to HSCC chemosensitivity. Then, we constructed the molecular network regulating chemosensitivity in HSCC. After that, we employed degree centrality (DC) and weighted centrality (WC) to test the significance of PPARG within the regulating network. Pathway enrichment was done to study the cofunctions of PPARG and the rest of the genes within the network. The findings of our study contribute to the construction of a comprehensive network that regulates HSCC chemosensitivity, consisting of 57 genes, including PPARG. Notably, within this network, PPARG demonstrates a ranking of #5 and #13 based on DC and WC, respectively. Moreover, PPARG is connected to 29 out of the 57 genes and plays roles in multiple functional groups. These top related genes include AKT1, TP53, PTEN, MAPK1, NOTCH1, BECN1, PTGS2, SPP1, and RAC1. PPARG gets enriched in several key functional groups that have been implicated in the regulation of chemosensitivity, including those associated with the response to nutrients, vitamins, and peptides, the cellular response to chemical stress, and the regulation of hormone secretion and growth. Our results emphasize the involvement of PPARG and its interconnectedness with other genes in the regulation of HSCC chemosensitivity.Copyright © 2023 Fanyong Kong et al.