Macelignan targets SLC7A11 to induce ferroptosis and modulate macrophage polarization via STAT6/PPAR-γ/KLF4 signaling.

Tumor-associated macrophages (TAMs) with an M2-like phenotype are key contributors to the development and immune escape of hepatocellular carcinoma (HCC). We show that the natural product macelignan (mace) reshapes macrophage polarization through a ferroptosis-driven mechanism. In HCC-conditioned macrophages, mace triggered glutathione depletion, lipid peroxidation, and downregulation of SLC7A11 and GPX4, consistent with the activation of ferroptosis. Blocking ferroptosis restored the M2 phenotype, confirming the mechanistic link. Computational modeling together with cellular thermal shift assays indicated a direct interaction between mace and SLC7A11. This interaction impaired the STAT6/PPAR-γ/KLF4 pathway and reduced the production of the chemokine CCL2, thereby reprogramming macrophages toward an antitumor phenotype. In this state, macrophages no longer enhanced HCC cell growth, migration, or epithelial-mesenchymal transition. In vivo, mace suppressed tumor growth and metastatic spread in xenograft models without detectable systemic toxicity. This work provides the first evidence that a natural product can reprogram TAMs through ferroptosis by targeting SLC7A11, offering a promising strategy for reshaping the immune microenvironment in HCC.