{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T10:26:52Z","timestamp":1777890412673,"version":"3.51.4"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    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\n                    <jats:italic>in vitro<\/jats:italic>\n                    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,\n                    <jats:italic>in vivo<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1822208","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:37:11Z","timestamp":1777613831000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tat-HSPE1 suppresses clear cell renal cell carcinoma growth through lysosome-dependent cell death"],"prefix":"10.3389","volume":"17","author":[{"given":"Lin","family":"Zhang","sequence":"first","affiliation":[{"name":"Tongren Hospital Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Tongren Hospital Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Department of Urology, Shanghai Tenth People\u2019s Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, Tongren Hospital Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, Tongren Hospital Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guang-Zhi","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Tongren Hospital Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0103425","DOI":"10.1128\/spectrum.01034-25","article-title":"Zika virus impairs autophagic flux in trabecular meshwork, and inhibition of autophagy restricts ocular viral transmission and associated pathology","volume":"13","author":"Ahmad","year":"2025","journal-title":"Microbiol. Spectr."},{"key":"B2","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41571-020-00455-z","article-title":"Beyond conventional immune-checkpoint inhibition - novel immunotherapies for renal cell carcinoma","volume":"18","author":"Braun","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.eururo.2018.08.036","article-title":"Epidemiology of renal cell carcinoma","volume":"75","author":"Capitanio","year":"2019","journal-title":"Eur. Urol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"900","DOI":"10.3390\/biom15060900","article-title":"Adaptation to arginine deprivation leads to a more aggressive, therapy-resistant phenotype in HNSCC cells","volume":"15","author":"Chen","year":"2025","journal-title":"Biomolecules"},{"key":"B5","doi-asserted-by":"publisher","first-page":"144242","DOI":"10.1016\/j.ijbiomac.2025.144242","article-title":"A novel peptide TCL6148 induces ferroptosis via the GOT1\/GPX4 pathway to enhance sunitinib sensitivity in renal cell carcinoma","volume":"313","author":"Chen","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3004","DOI":"10.1080\/15548627.2022.2056864","article-title":"An optimized protocol for immuno-electron microscopy of endogenous LC3","volume":"18","author":"De Mazi\u00e8re","year":"2022","journal-title":"Autophagy"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3616","DOI":"10.3390\/cancers14153616","article-title":"New therapeutic interventions for kidney carcinoma: looking to the future","volume":"14","author":"Dell'Atti","year":"2022","journal-title":"Cancers"},{"key":"B8","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell. Death Differ."},{"key":"B9","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.jconrel.2023.02.014","article-title":"Dual-responsive bioconjugates bearing a bifunctional adaptor for robust cytosolic peptide delivery","volume":"355","author":"Gao","year":"2023","journal-title":"J. Control. Release Official J. Control. Release Soc."},{"key":"B10","doi-asserted-by":"publisher","first-page":"108782","DOI":"10.1016\/j.bioorg.2025.108782","article-title":"Recent advances in HSP90 inhibitors as targeted cancer therapy: chemical scaffolds, isoform selectivity, and clinical progress","volume":"163","author":"Goel","year":"2025","journal-title":"Bioorg. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1074\/mcp.M800266-MCP200","article-title":"A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein","volume":"8","author":"Goudreault","year":"2008","journal-title":"Mol. and Cell. Proteomics MCP"},{"key":"B12","doi-asserted-by":"publisher","first-page":"14015","DOI":"10.1021\/acs.chemrev.7b00522","article-title":"Small bioactive peptides for biomaterials design and therapeutics","volume":"117","author":"Hamley","year":"2017","journal-title":"Chem. Rev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1039\/c8sc03390k","article-title":"The anti-apoptotic proteins NAF-1 and iASPP interact to drive apoptosis in cancer cells","volume":"10","author":"Iosub-Amir","year":"2019","journal-title":"Chem. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1007\/s12640-020-00164-6","article-title":"Neuroprotective effects of Necrostatin-1 against oxidative stress-induced cell damage: an involvement of cathepsin D inhibition","volume":"37","author":"Jantas","year":"2020","journal-title":"Neurotox. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1021\/ja311180x","article-title":"Acid-active cell-penetrating peptides for in vivo tumor-targeted drug delivery","volume":"135","author":"Jin","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2614","DOI":"10.1080\/15548627.2025.2512884","article-title":"RETREG1-mediated reticulophagy is activated by an ATF4-CEBPG\/C\/EBP\u03b3 heterodimer and confers protection against lipotoxicity","volume":"21","author":"Jin","year":"2025","journal-title":"Autophagy"},{"key":"B17","doi-asserted-by":"publisher","first-page":"eadw6064","DOI":"10.1126\/sciadv.adw6064","article-title":"In situ characterization of mitochondrial Hsp60-Hsp10 chaperone complex under folding stress","volume":"11","author":"Jung","year":"2025","journal-title":"Sci. Adv."},{"key":"B18","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/s41420-023-01544-5","article-title":"Dysregulation of a lncRNA within the TNFRSF10A locus activates cell death pathways","volume":"9","author":"Kaczynski","year":"2023","journal-title":"Cell. Death Discov."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1000206","DOI":"10.4172\/0974-8369.1000206","article-title":"Two faces of cathepsin D: physiological guardian angel and pathological demon","volume":"6","author":"Khalkhali-Ellis","year":"2014","journal-title":"Biol. Med. (Aligarh)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.eururo.2025.06.005","article-title":"Epidemiology of renal cancer: incidence, mortality, survival, genetic predisposition, and risk factors","volume":"88","author":"Larcher","year":"2025","journal-title":"Eur. Urol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"5698","DOI":"10.1016\/j.cell.2024.08.020","article-title":"TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival","volume":"187","author":"Lascaux","year":"2024","journal-title":"Cell."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e70162","DOI":"10.1002\/ctm2.70162","article-title":"A new peptide inhibitor of C1QBP exhibits potent anti-tumour activity against triple negative breast cancer by impairing mitochondrial function and suppressing homologous recombination repair","volume":"15","author":"Li","year":"2025","journal-title":"Clin. Transl. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"10799","DOI":"10.1021\/nn4040553","article-title":"Cell membranes open \u201cdoors\u201d for cationic nanoparticles\/biomolecules: insights into uptake kinetics","volume":"7","author":"Lin","year":"2013","journal-title":"ACS Nano"},{"key":"B24","doi-asserted-by":"publisher","first-page":"153384","DOI":"10.1016\/j.phymed.2020.153384","article-title":"Functional proteomic analysis reveals that fungal immunomodulatory protein reduced expressions of heat shock proteins correlates to apoptosis in lung cancer cells","volume":"80","author":"Lin","year":"2020","journal-title":"Phytomedicine Int. J. Phytotherapy Phytopharm."},{"key":"B25","doi-asserted-by":"publisher","first-page":"11653","DOI":"10.1021\/acs.chemrev.0c00963","article-title":"Design of polymeric carriers for intracellular peptide delivery in oncology applications","volume":"121","author":"Lv","year":"2021","journal-title":"Chem. Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"104191","DOI":"10.1016\/j.drudis.2024.104191","article-title":"Spotlight on HIV-Derived TAT peptide as a molecular shuttle in drug delivery","volume":"29","author":"Maani","year":"2024","journal-title":"Drug Discov. Today"},{"key":"B27","doi-asserted-by":"publisher","first-page":"hoaf076","DOI":"10.1093\/hropen\/hoaf076","article-title":"Organoids simulating the bovine oviduct mediate the embryo-maternal interface via extracellular vesicle-transmitted signaling","volume":"2026","author":"Menjivar","year":"2025","journal-title":"Hum. Reprod. Open"},{"key":"B28","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/s0022-1759(00)00137-x","article-title":"Purification of multiple heat shock proteins from a single tumor sample","volume":"237","author":"M\u00e9noret","year":"2000","journal-title":"J. Immunol. Methods"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3388","DOI":"10.3390\/cancers12113388","article-title":"Induction of lysosomal membrane permeabilization is a major event of FTY720-Mediated non-apoptotic cell death in human glioma cells","volume":"12","author":"Min","year":"2020","journal-title":"Cancers"},{"key":"B30","doi-asserted-by":"publisher","first-page":"4","DOI":"10.6004\/jnccn.2024.0008","article-title":"NCCN guidelines\u00ae insights: Kidney cancer, version 2.2024","volume":"22","author":"Motzer","year":"2024","journal-title":"J. Natl. Compr. Cancer Netw. JNCCN"},{"key":"B31","doi-asserted-by":"publisher","first-page":"114832","DOI":"10.1016\/j.biopha.2023.114832","article-title":"Evolving strategies and application of proteins and peptide therapeutics in cancer treatment","volume":"163","author":"Mukherjee","year":"2023","journal-title":"Biomed. and Pharmacother. = Biomedecine and Pharmacother."},{"key":"B32","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/s41573-020-00135-8","article-title":"Trends in peptide drug discovery","volume":"20","author":"Muttenthaler","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e2310569120","DOI":"10.1073\/pnas.2310569120","article-title":"Emergent properties of melanin-inspired peptide\/RNA condensates","volume":"120","author":"Netzer","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1042\/BST20240015","article-title":"Biogenesis of omegasomes and autophagosomes in mammalian autophagy","volume":"52","author":"Norell","year":"2024","journal-title":"Biochem. Soc. Trans."},{"key":"B35","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1042\/bse0550017","article-title":"Omegasomes: PI3P platforms that manufacture autophagosomes","volume":"55","author":"Roberts","year":"2013","journal-title":"Essays Biochem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1080\/15548627.2023.2280876","article-title":"MAP4K2 connects the hippo pathway to autophagy in response to energy stress","volume":"20","author":"Seo","year":"2024","journal-title":"Autophagy"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1080\/15548627.2025.2469207","article-title":"LAMP2-FLOT2 interaction enhances autophagosome-lysosome fusion to protect the septic heart in response to ILC2","volume":"21","author":"Shao","year":"2025","journal-title":"Autophagy"},{"key":"B38","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/nature15514","article-title":"Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death","volume":"526","author":"Shi","year":"2015","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e202403658","DOI":"10.1002\/chem.202403658","article-title":"Mechanistic insights into the apoptosis of cancer cells induced by a kinase-responsive peptide amphiphile","volume":"31","author":"Shimizu","year":"2025","journal-title":"Chem. Weinheim Der Bergstrasse, Ger."},{"key":"B40","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/nature11866","article-title":"Identification of a candidate therapeutic autophagy-inducing peptide","volume":"494","author":"Shoji-Kawata","year":"2013","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3233\/CBM-200410","article-title":"Overexpression of HSP10 correlates with HSP60 and Mcl-1 levels and predicts poor prognosis in non-small cell lung cancer patients","volume":"30","author":"Tang","year":"2021","journal-title":"Cancer Biomarkers Sect. A Dis. Markers"},{"key":"B42","doi-asserted-by":"publisher","first-page":"810","DOI":"10.4161\/auto.6486","article-title":"A dual role of p53 in the control of autophagy","volume":"4","author":"Tasdemir","year":"2008","journal-title":"Autophagy"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1038\/modpathol.2008.80","article-title":"Immunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomas","volume":"21","author":"T\u00eatu","year":"2008","journal-title":"Mod. Pathology An Official J. U. S. Can. Acad. Pathology, Inc"},{"key":"B44","doi-asserted-by":"publisher","first-page":"2412","DOI":"10.1002\/1878-0261.70006","article-title":"Targeting the MDM2-MDM4 interaction interface reveals an otherwise therapeutically active wild-type p53 in colorectal cancer","volume":"19","author":"Valentini","year":"2025","journal-title":"Mol. Oncol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e0075723","DOI":"10.1128\/jvi.00757-23","article-title":"Effects on exocytosis by two HSV-1 mutants unable to block autophagy","volume":"97","author":"Waisner","year":"2023","journal-title":"J. Virology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1080\/15548627.2023.2252301","article-title":"KPT330 promotes the sensitivity of glioblastoma to olaparib by retaining SQSTM1 in the nucleus and disrupting lysosomal function","volume":"20","author":"Wang","year":"2024","journal-title":"Autophagy"},{"key":"B47","doi-asserted-by":"publisher","first-page":"711","DOI":"10.3390\/antiox10050711","article-title":"Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism, and insulin sensitivity in the hypothalamus","volume":"10","author":"Wardelmann","year":"2021","journal-title":"Antioxidants Basel, Switz."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1080\/15548627.2022.2039535","article-title":"Chloroquine treatment induces secretion of autophagy-related proteins and inclusion of Atg8-family proteins in distinct extracellular vesicle populations","volume":"18","author":"Xu","year":"2022","journal-title":"Autophagy"},{"key":"B49","doi-asserted-by":"publisher","first-page":"6792","DOI":"10.1073\/pnas.1800562115","article-title":"Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor","volume":"115","author":"Yang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1080\/15548627.2024.2443945","article-title":"Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival","volume":"21","author":"Zein","year":"2025","journal-title":"Autophagy"},{"key":"B51","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.jconrel.2019.07.012","article-title":"Polypeptide-engineered DNA tetrahedrons for targeting treatment of colorectal cancer via apoptosis and autophagy","volume":"309","author":"Zhang","year":"2019","journal-title":"J. Control. Release Official J. Control. Release Soc."},{"key":"B52","doi-asserted-by":"publisher","first-page":"5710","DOI":"10.3390\/cancers14225710","article-title":"Tat-hspb1 suppresses clear cell renal cell carcinoma (ccRCC) growth via lysosomal membrane permeabilization","volume":"14","author":"Zhang","year":"2022","journal-title":"Cancers"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1735484","DOI":"10.3389\/fbioe.2025.1735484","article-title":"Necrostatin-1 alleviates temporomandibular joint osteoarthritis and inhibits chondrocyte senescence and necroptosis possibly via p53\/MAPK downregulation","volume":"13","author":"Zhang","year":"","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s12967-025-06091-4","article-title":"Endogenous peptide CBDP1 inhibits clear cell renal cell carcinoma progression by targeting USP5\/YTHDF2\/TRPM5 axis","volume":"23","author":"Zhang","year":"","journal-title":"J. Transl. Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s10495-025-02220-y","article-title":"Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease","volume":"31","author":"Zhang","year":"2026","journal-title":"Apoptosis An Int. J. Program. Cell. Death"},{"key":"B56","doi-asserted-by":"publisher","first-page":"390","DOI":"10.31083\/j.fbl2911390","article-title":"The PLCG2 inhibits tumor progression and mediates angiogenesis by VEGF signaling pathway in clear cell renal cell carcinoma","volume":"29","author":"Zhao","year":"2024","journal-title":"Front. Biosci. Landmark Ed."},{"key":"B57","doi-asserted-by":"publisher","first-page":"15","DOI":"10.7150\/ijbs.83586","article-title":"Role of YAP signaling in regulation of programmed cell death and drug resistance in cancer","volume":"20","author":"Zhou","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"B58","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/cr.2007.36","article-title":"Bcl-2 cleavages at two adjacent sites by different caspases promote cisplatin-induced apoptosis","volume":"17","author":"Zhu","year":"2007","journal-title":"Cell. Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s13045-024-01601-1","article-title":"Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies","volume":"17","author":"Zuo","year":"2024","journal-title":"J. Hematol. and Oncol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1822208\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:37:12Z","timestamp":1777613832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1822208\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,1]]},"references-count":59,"alternative-id":["10.3389\/fphar.2026.1822208"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1822208","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,1]]},"article-number":"1822208"}}