BACKGROUND: The Jumonji domain-containing protein 6 (JMJD6), a histone arginine demethylase, is known to have a multifaceted and significant role on cancer progression. However, the specific function and mechanism of JMJD6 in non-small cell lung cancer (NSCLC) have yet to be fully elucidated. METHODS: The elevated expression of JMJD6 in lung cancer tissues was confirmed through a combination of bioinformatics and immunohistochemical analysis. Utilizing lung cancer cell lines H460, H157, A549, and H1299, we further investigated the impact of JMJD6 on various cellular processes such as ferroptosis, proliferation, migration, and invasion both in vivo and in vitro. The acetylation of JMJD6 was characterized using immunoprecipitation, co-immunoprecipitation, GST pull down, and immunofluorescence techniques. The regulatory role of JMJD6 acetylation in ferroptosis was assessed by measuring levels of ROS, MDA, and JC-1. WB, qRT-PCR, ChIP and MeRIP techniques were employed to investigate the relationship between the JMJD6 acetylation/METTL14/m6A/SLC3A2 axis. RESULTS: This study revealed elevated levels of JMJD6 in tumor tissue, with high expression correlating strongly with advanced clinical stage in lung cancer patients, and identified JMJD6 as a significantly poor prognostic factor for lung cancer. Functional experiments verified that ectopic overexpression of JMJD6 enhanced the proliferation and migratory capacities of lung cancer cells, while JMJD6 knockdown showed opposite effects. We further find that JMJD6 functions as a negative modulator in regulating ferroptosis process. Mechanistically, JMJD6 affects METTL14 expression in an arginine demethylase dependent manner, and mediates m6A modification of SLC3A2 to regulate its expression level, thereby affecting the sensitivity of lung cancer cells to ferroptosis. Besides, our findings indicate that acetyltransferase p300/CBP associated factor (PCAF) interacts with and acetylates JMJD6 at lysine 375. Acetylation weakens the activity of JMJD6 demethylase, thereby enhancing METTL14 expression and affecting its mediated m6A modification to regulate SLC3A2. Acetylation at lysine 375 also augment the modulation of ferroptosis in lung cancer cells by JMJD6, consequently impeding the lung cancer progression. CONCLUSION: Taken together, we elucidated the JMJD6 acetylation/METTL14/m6A/SLC3A2 axis as a key mediator of lung cancer progression, indicating that JMJD6 may serve as a potentially prognostic biomarker and therapeutic target for NSCLC.