Paclitaxel (PTX) resistance limits cervical cancer therapy. Ferroptosis suppression via GPX4 and redox remodeling has emerged as a resistance mechanism, but upstream regulators remain unclear. To determine whether ANO6 drives PTX resistance by inhibiting ferroptosis and to define the ANO6-GPX4 axis mechanistically and therapeutically. Transcriptomic analyses, immunohistochemistry on clinical specimens, and cervical cancer cell models with gain/loss of ANO6 were combined with ferroptosis assays, mitochondrial imaging, apoptosis/viability assays, and Co-IP/CHX chase to assess ANO6-GPX4 interaction and stability. GPX4 transcriptional control was probed by ChIP-qPCR and dual-luciferase. PTX sensitivity was tested in vitro and in xenografts, with or without the ferroptosis inducer RSL3. ANO6 was overexpressed in cervical cancer and associated with worse prognosis. ANO6 knockdown reduced GPX4, SLC7A11, and NRF2, increased ACSL4, elevated lipid peroxidation and iron load, disrupted mitochondrial integrity, and heightened PTX cytotoxicity; ANO6 overexpression had opposite effects. ANO6 physically associated with GPX4 and preserved its protein stability; NRF2 enhanced GPX4 promoter activity, supporting a dual (post-translational/transcriptional) maintenance of GPX4 under ANO6 control. In PTX-resistant cells, ANO6 was upregulated; its depletion restored ferroptosis and PTX sensitivity, whereas GPX4 overexpression rescued resistance. In vivo, ANO6 overexpression promoted tumor growth and PTX resistance, while PTX + RSL3 synergistically suppressed tumors and reversed GPX4-axis signaling. ANO6 confers PTX resistance by sustaining GPX4-dependent ferroptosis evasion and mitochondrial homeostasis. Targeting the ANO-GPX4 axis, alone or combined with ferroptosis induction, may improve chemotherapy sensitivity in cervical cancer.
Cao et al. (2026) studied this question.