Abstract: Background　The E6 oncoprotein of human papillomavirus type 16 (HPV16) is a key factor in cervical carcinogenesis, yet its mechanisms mediating cell proliferation and apoptosis remain to be elucidated.Objective　To investigate whether HPV16 E6 activates the NF-κB pathway via FOXC1 and elucidate the regulatory mechanism of FOXC1 in proliferation and apoptosis of HPV-positive cervical cancer cells.Methods　Western blot was used to detect the expression of FOXC1, Ki-67 and Caspase-3 in cervical cancer and normal cervical tissue. HPV-positive cervical cancer cell models (Siha, Hela) with FOXC1 knockdown (sh-FOXC1) were constructed, and Western blot was used to detect the expression changes of Caspase-3, Bcl-2, Bax, phosphorylated NF-κB p65 (p-NF-κB p65) and NF-κB p65 in the cells after FOXC1 knockdown. qRT-PCR was used to detect the expression levels of NF-κB downstream pro-inflammatory factors IL-6 and TNF-α mRNA in each group of cells. Colony formation and TUNEL apoptosis assays were used to analyze the effects of FOXC1 knockdown on cell proliferation and apoptosis. Overexpression of HPV16 E6 in the sh-FOXC1 group of Siha cells was used to verify the regulatory relationship between HPV16 E6 and the FOXC1-NF-κB axis, and Western blot was used to detect the expression changes of E6, FOXC1, Caspase-3, Bcl-2, Bax, p-NF-κB p65 and NF-κB p65 in each group of cells. Colony formation and TUNEL apoptosis assays were used to detect the changes in cell proliferation and apoptosis ability in each group.Results　FOXC1 protein expression was 4.61-fold higher in tumor tissues compared to normal controls (P＜0.01), accompanied by a 2.17-fold increase in Ki-67 and a significant reduction of Caspase-3 to 38.82% of normal levels. In cell lines, FOXC1 expression showed 5.43-fold (SiHa) and 21.41-fold (HeLa) elevation versus C33A cells, and 6.41-fold/25.49-fold increases relative to immortalized HCerEpiC cells (all P＜0.01). FOXC1 knockdown (sh-FOXC1) induced pro-apoptotic effects, with Caspase-3 and Bax expression increasing 1.94-fold and 1.66-fold respectively in SiHa cells (P＜ 0.05), while anti-apoptotic Bcl-2 and p-NF- κB p65 decreased to 55.41% and 51.09% (P＜0.05). Total NF- κB p65 remained unchanged (P＞0.05). Correspondingly, qRT-PCR demonstrated significant downregulation of NF-κB-dependent cytokines IL-6 and TNF-α mRNA (P＜0.01). Functional assays showed sh-FOXC1 reduced colony formation by 46.46% (to 53.54% of control) and increased apoptosis 2.73-fold (P＜0.01), with consistent results in HeLa cells. Rescue experiments through HPV16 E6 overexpression (sh-FOXC1-OE E6) reversed these effects: E6, FOXC1, p-NF-κB p65 and Bcl-2 rebounded 1.36-, 4.17-, 4.26- and 3.34-fold respectively (P＜0.05), while Caspase-3/Bax declined to 61.77%/68.94% (P＜0.05). This was associated with 2.83-fold increased colony formation (P＜0.01) and reduced apoptosis to 45.54% of knockdown levels (P＜0.01).Conclusion　HPV16 E6 may activate the NF-κB pathway by upregulating FOXC1, thereby promoting the proliferation of cervical cancer cells and inhibiting apoptosis. These findings suggest that FOXC1 could potentially serve as a therapeutic target for HPV-positive cervical cancer.