This study examines the antitumor properties of HM in NSCLC and elucidates its molecular mechanisms. The experimental findings indicate that HM markedly suppresses the proliferation and migration of A549 and H1299 cells, induces cell cycle arrest, and promotes apoptosis in a dose-dependent manner. Subsequent investigations reveal that HM upregulates ferroptosis marker genes (PTGS2, ACSL4, LPCAT3) while downregulating antioxidant genes (GPX4, SLC7A11, NFE2L2), resulting in intracellular iron accumulation and lipid peroxidation, thereby triggering ferroptosis. Through bioinformatics analysis and molecular dynamics simulations, PDE4D was identified as a critical target of HM. Further validation confirmed that HM binds to PDE4D and inhibits the PI3K-AKT-Nrf2 signaling pathway, leading to the suppression of GPX4 and SLC7A11 expression. Rescue experiments demonstrated that PDE4D overexpression counteracted HM’s inhibitory effects on cell proliferation and migration, as well as its induction of apoptosis and ferroptosis. Subcutaneous xenograft models in nude mice corroborated that HM impedes tumor growth by targeting PDE4D, with no significant hepatorenal toxicity observed. This study elucidates the molecular mechanism by which HM induces ferroptosis via the PDE4D-PI3K-AKT-Nrf2 signaling axis, offering experimental evidence and identifying a potential therapeutic target for the treatment of NSCLC.