HPGD Inhibited Natural Killer Cell Activation and Enhanced Autophagy to Promote the Progression of Papillary Thyroid Cancer by Activating the JAK2/STAT3 Pathway

Background: HPGD is implicated in multiple cancers, but its role in papillary thy-roid cancer (PTC) remains unclear. This study aimed to investigate the role and potential mechanism of HPGD in PTC. Materials and Methods: HPGD expression in PTC was analyzed using TCGA data. Kaplan-Meier survival and receiver operator characteristic (ROC) analyses were conducted to evaluate its prognostic and diagnostic value. Functional experiments were performed in TPC-1 cells with HPGD knockdown and overexpression to assess cell proliferation, migration, invasion, autophagy, and JAK/STAT signaling using colony formation, wound-healing, Transwell, and western blot analyses. The tumor immune microenvironment (TIME) was analyzed based on immune infiltration scores. The effect of HPGD on natural killer (NK) cell cytotoxicity was evaluated using a co-culture system with TPC-1 cells. Results: High HPGD expression was associated with poor prognosis. Functional experiments demonstrated that HPGD overexpression promoted PTC cell proliferation, migration, and in-vasion, while its knockdown had the opposite effect. Mechanistically, HPGD activated au-tophagy and the JAK2/STAT3 pathway. In the TIME, high HPGD expression was associated with increased immune and stromal scores but reduced NK cell infiltration. Moreover, HPGD overexpression suppressed NK cell cytotoxicity by reducing ICAM-1 expression, enhancing autophagy, and activating JAK2/STAT3. Results: High HPGD expression was associated with poor prognosis. Functional experiments demonstrated that HPGD overexpression promoted PTC cell proliferation, migration, and in-vasion, while its knockdown had the opposite effect. Mechanistically, HPGD activated au-tophagy and the JAK2/STAT3 pathway. In the TIME, high HPGD expression was associated with increased immune and stromal scores but reduced NK cell infiltration. Moreover, HPGD overexpression suppressed NK cell cytotoxicity by reducing ICAM-1 expression, enhancing autophagy, and activating JAK2/STAT3. Discussion: This study reveals that HPGD exerts a tumor-promoting and immune-suppressive role in PTC, contrasting with its tumor-suppressive effects in other cancers. Its regulation of autophagy, JAK2/STAT3 signaling, and NK cell cytotoxicity highlights a cancer-type-specific mechanism. Conclusion: These findings suggest that targeting HPGD could be a potential therapeutic strat-egy for PTC.