Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality worldwide, emphasizing the need for novel therapeutic strategies. In this study, we demonstrate that homoyessotoxin (hYTXs), a marine-derived natural compound, exerts potent anti-NSCLC progression. Network pharmacology, molecular docking, molecular dynamics simulations, and SPR analysis confirmed a strong binding affinity between hYTXs and EGFR. Mechanistically, hYTXs disrupted EGFR trafficking by accelerating its endocytosis and enhancing its accumulation within lysosomes, thereby accelerating receptor degradation without altering EGFR mRNA levels. CHX chase and lysosomal inhibition assays further verified that hYTXs downregulated EGFR through post-translational regulation. This degradation led to suppression of downstream PI3K/AKT/ERK signaling, reduced phosphorylation of FOXO3a and p70S6K, and enhanced PTEN nuclear translocation. Functionally, hYTXs induced apoptosis, oxidative stress, S-phase arrest, mitochondrial dysfunction, and DNA damage in A549 cells, with comparable inhibitory potency in EGFR-mutant lines (PC9, H1975) but minimal cytotoxicity toward normal lung epithelial cells. In vivo, hYTXs significantly inhibited tumor growth and exhibited excellent safety based on serum biochemistry and lung histology. Collectively, hYTXs represents a promising next-generation EGFR-targeting compound that overcomes kinase-mutation-driven resistance by promoting receptor degradation rather than kinase inhibition.

Emerging evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) is strongly associated with the occurrence and progression of breast cancer. Herein, we identified ubiquitin specific peptidase 30 antisense RNA 1 (USP30-AS1) as a markedly upregulated lncRNA in breast cancer tissues, and the transcription factor SPI1 functions upstream to regulate the expression of USP30-AS1. Gene set enrichment analysis suggests that USP30-AS1 may regulate cell proliferation. Knockdown of USP30-AS1 suppresses breast cancer cell proliferation and tumor growth by up-regulating CDKN1A/p21. Mechanistically, USP30-AS1 exhibits dual localization within breast cancer cells. In the cytoplasm, it interacts with HnRNPF, disrupting its binding to the p21 3′UTR, which destabilizes p21 mRNA and ultimately reduces p21 expression. In the nucleus, USP30-AS1 suppresses p21 transcription by enhancing the activity of c-Myc, a known transcriptional repressor of p21. USP30-AS1 binds to enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, and prevents EZH2 from binding to the c-Myc promoter. This promotes epigenetic up-regulation of c-Myc by reducing H3K27 trimethylation. Together, these findings demonstrate the critical role of USP30-AS1 in breast cancer progression through HnRNPF/p21 and EZH2/c-Myc/p21 axes, highlighting its potential as a therapeutic target for breast cancer treatment.