Dapk2 dysfunction leads to Mic60 lactylation and mitochondrial metabolic reprogramming, promoting lung cancer EGFR-TKI resistance and metastasis.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is often linked to tumor metastasis, making control of metastasis crucial. Here, we identified a critical signaling hub responsible for cancer metastasis and resistance development: mitochondrial cristae remodeling and metabolic reprogramming, using an anoikis-resistant cell model and a mouse tail vein metastasis model. EGFR-TKI-resistant cells exhibited stronger anoikis resistance (AR) and mitochondrial metabolism compared with sensitive cells, making them more prone to metastasis. Dysfunction of death-associated protein kinase 2 (Dapk2) altered Mic60 protein in mitochondrial cristae, increasing the abundance and compactness of the cristae and activating mitochondrial metabolism. Lactylation of the Mic60 protein may be the critical mechanism affecting the restructuring of mitochondrial cristae and activating mitochondrial metabolism. Our findings elucidate the role and underlying mechanisms of mitochondrial morphological dynamics and metabolic reprogramming in resistance and metastasis, offering potential therapeutic targets to overcome EGFR-TKI resistance and metastasis in lung cancer.