The YTHDF3-DT/miR-301a-3p /INHBA axis attenuates autophagy-dependent ferroptosis in lung adenocarcinoma.

YTHDF3-DT, a long non-coding RNA (lncRNA) significantly upregulated in lung adenocarcinoma (LUAD), is associated with poor patient prognosis and plays critical roles in LUAD progression. Clinical data and in vitro analyses revealed that YTHDF3-DT expression correlates with worse overall survival and increased lymph node metastasis in LUAD patients. Functional studies demonstrated that YTHDF3-DT activates the TGF-β and PI3K/Akt/mTOR signaling pathways via INHBA, a key target influenced by YTHDF3-DT. Mechanistically, YTHDF3-DT stabilizes INHBA mRNA by acting as a competing endogenous RNA (ceRNA) for miR-301a-3p, forming a YTHDF3-DT/miR-301a-3p/INHBA axis. This axis regulates ferroptosis in an autophagy-dependent manner in LUAD cells, with YTHDF3-DT promoting cell survival by altering autophagic activity and mitigating ferroptosis-induced cell death. In vivo experiments further validated the role of YTHDF3-DT in tumor growth and ferroptosis regulation, highlighting its potential as a therapeutic target in LUAD. Our data contribute toward a significant mechanistic understanding of the molecules involved in the crosstalk between ferroptosis and autophagy, providing potential therapeutic targets to complement the existing therapies for overcoming the developed resistance in patients with LUAD.