Cytochrome c-mediated mitochondrial apoptosis activation underpins THz wave-induced melanoma cell death

Cutaneous melanoma, a malignancy with a rising global incidence, remains a therapeutic challenge due to drug resistance despite advances in immunotherapies. We identified 0.1 THz waves as a precise therapeutic modality that induced melanoma-specific apoptosis via a caspase-independent pathway, while preserving the viability, proliferation, and migratory capacity of normal fibroblasts. Proteomics revealed that mitochondria were the main target of THz radiation and Cytochrome c1 (Cyc1) was the most significantly altered molecule, closely related to Cytochrome c (Cyt c). Notably, molecular dynamics simulations showed that THz radiation did not induce significant structural changes in Cyt c, but could lead to the release of Cyt c by causing mitochondrial perforation. Experimental studies further showed that melanoma cells could trigger the release of Cyt c and the apoptosis inducing factor (AIF) by synergistically opening mitochondrial permeability transition pores (mPTP) and mitochondrial apoptosis inducing channels (MAC), thereby initiating the apoptosis program. Further validation using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases confirmed that AIF was a critical determinant in the prognosis of melanoma. In summary, the mechanism by which THz waves specifically activate the cascade of mitochondrial apoptosis through the Cyt c-AIF-dependent pathway provides theoretical support for their use as a highly targeted and novel therapeutic strategy.