Tat-HSPE1 suppresses clear cell renal cell carcinoma growth through lysosome-dependent cell death

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer; however, first-line therapeutic agents show limited efficacy in patients with advanced disease. Bioactive peptides have emerged as promising candidates for anticancer therapy. In this study, a novel peptide derived from Heat Shock Protein Family E Member 1 (HSPE1) was identified by peptidomics analysis of human ccRCC tissues and paired adjacent normal tissues. We then engineered a novel fusion peptide designated Tat-HSPE1. Tat-HSPE1 selectively induced in vitro cell death in ccRCC cells while exerting minimal cytotoxic effects on normal epithelial cells and other tumor cell types. Analyses on the potential mechanism revealed that Tat-HSPE1 induced DNA damage, caspase-independent apoptosis, and lysosomal membrane permeabilization. Following cellular uptake, Tat-HSPE1 preferentially accumulated within the nucleolar compartment, where it interacted with CTTNBP2NL, a newly identified negative regulator of autophagy. This interaction promoted the translocation of CTTNBP2NL from the nucleus to the cytoplasm, facilitating the activation of autophagic processes. Furthermore, in vivo experiments demonstrated that Tat-HSPE1 significantly suppressed xenograft tumor growth. These findings indicate that Tat-HSPE1 represents a promising peptide-based therapeutic candidate for the treatment of ccRCC.