{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:09:19Z","timestamp":1780510159611,"version":"3.54.1"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81903852"],"award-info":[{"award-number":["81903852"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Capsaicin, a natural compound, has demonstrated antitumor efficacy in estrogen receptor-positive breast cancer (ER-positive BC). However, its downstream molecular targets and mechanisms remain poorly understood, particularly those linked to metabolic reprogramming and immune modulation. This study aimed to identify capsaicin-responsive genes and explore their roles in ER-positive BC progression and tumor microenvironment remodeling. Bioinformatic analysis was performed on the GSE64155 dataset from GEO to screen differentially expressed genes (DEGs) in capsaicin-treated ER-positive BC. Functional enrichment (GO\/KEGG) and protein-protein interaction (PPI) network analyses were performed to prioritize key genes. Experimental validation included qPCR and Western blotting to assess gene and protein expression in capsaicin-treated cells. Clinical relevance was evaluated using TCGA expression data, survival analysis (overall survival [OS], relapse-free survival [RFS], and distant metastasis-free survival [DMFS]), and immunohistochemistry (IHC) in BC tissues. Immune cell infiltration was analyzed via the CIBERSORT algorithm. SHMT2 and GARS were identified as the most significant capsaicin-responsive genes. Both genes were overexpressed in BC tissues and may be associated with a poor prognosis in patients with ER-positive BC. Capsaicin significantly reduced SHMT2 and GARS expression at the mRNA and protein levels. Immune infiltration analysis indicated that high SHMT2 and GARS expression may be associated with altered immune cell infiltration patterns. This study identifies SHMT2 and GARS as novel downstream targets of capsaicin in ER-positive BC and links their known oncogenic functions to a potential new mechanism underlying the antitumor effects of capsaicin.<\/jats:p>","DOI":"10.1371\/journal.pone.0350841","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:27:55Z","timestamp":1780507675000},"page":"e0350841","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of potential key genes that respond to capsaicin treatment in ER-positive breast cancer: An integrated analysis"],"prefix":"10.1371","volume":"21","author":[{"given":"Long","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2283-997X","authenticated-orcid":true,"given":"Wei","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"pone.0350841.ref001","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"H Sung","year":"2021","journal-title":"CA: a cancer journal for clinicians"},{"issue":"14","key":"pone.0350841.ref002","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.2217\/fon.14.110","article-title":"Estrogen and progesterone receptors in breast cancer","volume":"10","author":"C-H Yip","year":"2014","journal-title":"Future Oncol"},{"issue":"2","key":"pone.0350841.ref003","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1093\/annonc\/mdx651","article-title":"Characterization of male breast cancer: results of the EORTC 10085\/TBCRC\/BIG\/NABCG International Male Breast Cancer Program","volume":"29","author":"F Cardoso","year":"2018","journal-title":"Ann Oncol"},{"issue":"5","key":"pone.0350841.ref004","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1186\/s13058-014-0455-1","article-title":"Functional variants at the 21q22.3 locus involved in breast cancer progression identified by screening of genome-wide estrogen response elements","volume":"16","author":"C-N Hsiung","year":"2014","journal-title":"Breast Cancer Res"},{"key":"pone.0350841.ref005","doi-asserted-by":"crossref","first-page":"5189490","DOI":"10.1155\/2019\/5189490","article-title":"Pharmacotherapeutics and Molecular Mechanism of Phytochemicals in Alleviating Hormone-Responsive Breast Cancer","volume":"2019","author":"S Rampogu","year":"2019","journal-title":"Oxid Med Cell Longev"},{"issue":"1","key":"pone.0350841.ref006","doi-asserted-by":"crossref","first-page":"881","DOI":"10.3892\/mmr.2015.4623","article-title":"Capsaicin enhances anti-proliferation efficacy of pirarubicin via activating TRPV1 and inhibiting PCNA nuclear translocation in 5637 cells","volume":"13","author":"L Zheng","year":"2016","journal-title":"Mol Med Rep"},{"issue":"10","key":"pone.0350841.ref007","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1177\/0960327110396530","article-title":"Capsaicin may induce breast cancer cell death through apoptosis-inducing factor involving mitochondrial dysfunction","volume":"30","author":"HC Chang","year":"2011","journal-title":"Hum Exp Toxicol"},{"issue":"2","key":"pone.0350841.ref008","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/onc.2009.335","article-title":"Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR\/HER-2 pathway","volume":"29","author":"NH Thoennissen","year":"2010","journal-title":"Oncogene"},{"issue":"5","key":"pone.0350841.ref009","first-page":"169","article-title":"Development of 68Ga-SCN-DOTA-Capsaicin as an Imaging Agent Targeting Apoptosis and Cell Cycle Arrest in Breast Cancer","volume":"32","author":"JY Lee","year":"2017","journal-title":"Cancer Biother Radiopharm"},{"issue":"8","key":"pone.0350841.ref010","doi-asserted-by":"crossref","first-page":"3430","DOI":"10.1021\/acs.molpharmaceut.9b00209","article-title":"Co-Delivery of Paclitaxel by a Capsaicin Prodrug Micelle Facilitating for Combination Therapy on Breast Cancer","volume":"16","author":"Y Lan","year":"2019","journal-title":"Mol Pharm"},{"key":"pone.0350841.ref011","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12935-019-0769-2","article-title":"Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase","volume":"19","author":"BG S\u00e1nchez","year":"2019","journal-title":"Cancer Cell Int"},{"issue":"1","key":"pone.0350841.ref012","doi-asserted-by":"crossref","DOI":"10.5489\/cuaj.784","article-title":"Capsaicin may slow PSA doubling time: case report and literature review","volume":"4","author":"B Jankovic","year":"2010","journal-title":"Can Urol Assoc J"},{"issue":"2","key":"pone.0350841.ref013","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.3892\/or.2015.4055","article-title":"Capsaicin causes inactivation and degradation of the androgen receptor by inducing the restoration of miR-449a in prostate cancer","volume":"34","author":"L Zheng","year":"2015","journal-title":"Oncol Rep"},{"issue":"2","key":"pone.0350841.ref014","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.molcel.2015.12.014","article-title":"Serine Metabolism Supports the Methionine Cycle and DNA\/RNA Methylation through De Novo ATP Synthesis in Cancer Cells","volume":"61","author":"ODK Maddocks","year":"2016","journal-title":"Mol Cell"},{"issue":"11","key":"pone.0350841.ref015","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1158\/0008-5472.CAN-13-2683","article-title":"Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes","volume":"74","author":"GY Lee","year":"2014","journal-title":"Cancer Res"},{"key":"pone.0350841.ref016","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/s43018-020-0080-0","article-title":"The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing","volume":"1","author":"S Parsa","year":"2020","journal-title":"Nat Cancer"},{"key":"pone.0350841.ref017","doi-asserted-by":"crossref","first-page":"7430","DOI":"10.12659\/MSM.917435","article-title":"High expression of serine hydroxymethyltransferase 2 indicates poor prognosis of gastric cancer patients","volume":"25","author":"H Shi","year":"2019","journal-title":"Medical Science Monitor: International Medical Journal of Experimental and Clinical Research"},{"key":"pone.0350841.ref018","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.ctrv.2016.03.005","article-title":"Metabolic phenotype of bladder cancer","volume":"45","author":"F Massari","year":"2016","journal-title":"Cancer Treat Rev"},{"key":"pone.0350841.ref019","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.1111\/febs.14610","article-title":"The catalytic activity of serine hydroxymethyltransferase is essential for de novo nuclear dTMP synthesis in lung cancer cells. The","volume":"285","author":"G Giardina","year":"2018","journal-title":"FEBS journal"},{"issue":"5","key":"pone.0350841.ref020","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.3892\/or.2016.5112","article-title":"Prognostic and therapeutic value of mitochondrial serine hydroxyl-methyltransferase 2 as a breast cancer biomarker","volume":"36","author":"L Zhang","year":"2016","journal-title":"Oncol Rep"},{"key":"pone.0350841.ref021","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.2147\/OTT.S82433","article-title":"Positive correlation between expression level of mitochondrial serine hydroxymethyltransferase and breast cancer grade","volume":"8","author":"K Yin","year":"2015","journal-title":"Onco Targets Ther"},{"issue":"7","key":"pone.0350841.ref022","first-page":"3405","article-title":"SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer","volume":"12","author":"S-Y Xie","year":"2022","journal-title":"Am J Cancer Res"},{"key":"pone.0350841.ref023","doi-asserted-by":"crossref","first-page":"11169","DOI":"10.2147\/CMAR.S272274","article-title":"Circ_0072995 promotes cell carcinogenesis via up-regulating miR-149-5p-mediated SHMT2 in breast cancer","volume":"12","author":"C Qi","year":"2020","journal-title":"Cancer management and research"},{"issue":"1","key":"pone.0350841.ref024","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s13058-017-0905-7","article-title":"Proteomic profiling of breast cancer metabolism identifies SHMT2 and ASCT2 as prognostic factors","volume":"19","author":"S Bernhardt","year":"2017","journal-title":"Breast Cancer Res"},{"issue":"1","key":"pone.0350841.ref025","article-title":"ERR\u03b1 activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption","volume":"40","author":"X Li","year":"2020","journal-title":"Biosci Rep"},{"issue":"9","key":"pone.0350841.ref026","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.3390\/cells8091048","article-title":"Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism","volume":"8","author":"I Marrocco","year":"2019","journal-title":"Cells"},{"issue":"7","key":"pone.0350841.ref027","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.3390\/ijms20071660","article-title":"Capsaicin Targets Lipogenesis in HepG2 Cells Through AMPK Activation, AKT Inhibition and PPARs Regulation","volume":"20","author":"A Bort","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"6","key":"pone.0350841.ref028","doi-asserted-by":"crossref","DOI":"10.1111\/acel.13391","article-title":"SIRT2-knockdown rescues GARS-induced Charcot-Marie-Tooth neuropathy","volume":"20","author":"Y Zhao","year":"2021","journal-title":"Aging Cell"},{"key":"pone.0350841.ref029","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3389\/fneur.2018.00571","article-title":"A novel mutation of GARS in a Chinese family with distal hereditary motor neuropathy type V","volume":"9","author":"X Yu","year":"2018","journal-title":"Frontiers in Neurology"},{"issue":"5","key":"pone.0350841.ref030","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1002\/ajmg.a.61544","article-title":"GARS-related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment","volume":"182","author":"R Markovitz","year":"2020","journal-title":"Am J Med Genet A"},{"issue":"11","key":"pone.0350841.ref031","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1038\/s41418-018-0099-2","article-title":"A novel endogenous damage signal, glycyl tRNA synthetase, activates multiple beneficial functions of mesenchymal stem cells","volume":"25","author":"S-R Park","year":"2018","journal-title":"Cell Death Differ"},{"issue":"8","key":"pone.0350841.ref032","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nsmb.3250","article-title":"Neddylation requires glycyl-tRNA synthetase to protect activated E2","volume":"23","author":"Z Mo","year":"2016","journal-title":"Nat Struct Mol Biol"},{"issue":"6","key":"pone.0350841.ref033","first-page":"1453","article-title":"Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer","volume":"15","author":"S Yano","year":"2006","journal-title":"Oncol Rep"},{"key":"pone.0350841.ref034","doi-asserted-by":"crossref","first-page":"914332","DOI":"10.3389\/fonc.2022.914332","article-title":"SHMT2 regulates serine metabolism to promote the progression and immunosuppression of papillary renal cell carcinoma","volume":"12","author":"W Kong","year":"2022","journal-title":"Front Oncol"},{"key":"pone.0350841.ref035","doi-asserted-by":"crossref","first-page":"110302","DOI":"10.1016\/j.cellsig.2022.110302","article-title":"GARS is implicated in poor survival and immune infiltration of hepatocellular carcinoma","volume":"94","author":"J Wang","year":"2022","journal-title":"Cell Signal"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0350841","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:28:02Z","timestamp":1780507682000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0350841"}},"subtitle":[],"editor":[{"given":"V V SATHIBABU","family":"UDDANDRAO","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0350841","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]}}}