{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:59:29Z","timestamp":1790071169941,"version":"4.0.1"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004826","name":"Beijing Municipal Natural Science Foundation","doi-asserted-by":"publisher","award":["7234412"],"award-info":[{"award-number":["7234412"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Objective: Esophageal cancer (ESCA) has poor prognosis and lacks reliable biomarkers. This study aimed to construct a mitochondrial energy metabolism-related prognostic model and identify key regulatory genes. Methods: TCGA-ESCA and GSE53625 data were used as training and validation cohorts, respectively. Mitochondrial energy metabolism scores were calculated by ssGSEA. Differential expression analysis and WGCNA identified key genes, followed by consensus clustering, Cox\/LASSO regression, enrichment analysis, immune infiltration, TIDE evaluation, and nomogram development. INHBA knockdown or overexpression was performed in KYSE-150 and TE-1 cells to assess malignant phenotypes, mitochondrial function, EMT markers, and Smad2\/3 signaling, with SB431542 used for pathway blockade. Results: High mitochondrial energy metabolism scores predicted poorer overall survival. A total of 124 key genes were identified, and three molecular subtypes were established, with Cluster 2 showing the worst prognosis. A four-gene signature comprising COL11A1, INHBA, TNFAIP6, and POSTN stratified patients into high- and low-risk groups in both cohorts. High-risk tumors were enriched in extracellular matrix remodeling, cell adhesion, inflammatory response, hypoxia, angiogenesis, and PI3K-Akt signaling, whereas oxidative phosphorylation was more active in low-risk tumors. The high-risk group had higher TIDE scores, suggesting poorer immunotherapy response. The nomogram incorporating risk group and M stage showed limited discrimination after bootstrap correction. In vitro, INHBA promoted proliferation, migration, invasion, EMT, mitochondrial membrane potential, ATP production, and oxidative phosphorylation. SB431542 partially reversed these effects. Conclusions: This MEMRG-based model predicts ESCA prognosis and immune features. INHBA promotes ESCA progression by activating Smad2\/3-mediated EMT and mitochondrial metabolic reprogramming, suggesting its potential as a prognostic biomarker and therapeutic target.<\/jats:p>","DOI":"10.3390\/biom16091367","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1367","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Construction of an Esophageal Cancer Prognostic Model Based on Mitochondrial Energy Metabolism-Related Genes and Mechanism of INHBA in Promoting Malignant Progression via the Smad2\/3 Pathway"],"prefix":"10.3390","volume":"16","author":[{"given":"Jinping","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No.28 Fuxing Road, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5491-4096","authenticated-orcid":false,"given":"Yi","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No.28 Fuxing Road, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Huikai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No.28 Fuxing Road, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Bozong","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No.28 Fuxing Road, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Enqiang","family":"Linghu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, No.28 Fuxing Road, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3108","DOI":"10.1097\/CM9.0000000000003420","article-title":"Global esophageal cancer epidemiology in 2022 and predictions for 2050: A comprehensive analysis and projections based on GLOBOCAN data","volume":"137","author":"Qi","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network, Analysis Working Group: Asan University, BC Cancer Agency, Brigham and Women\u2019s Hospital, Broad Institute, Brown University, Case Western Reserve University, Dana-Farber Cancer Institute, Duke University, and Greater Poland Cancer Centre (2017). Integrated genomic characterization of oesophageal carcinoma. Nature, 541, 169\u2013175.","DOI":"10.1038\/nature20805"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1053\/j.gastro.2022.05.054","article-title":"The Global Landscape of Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma Incidence and Mortality in 2020 and Projections to 2040: New Estimates from GLOBOCAN 2020","volume":"163","author":"Morgan","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S0140-6736(21)01234-4","article-title":"Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study","volume":"398","author":"Sun","year":"2021","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1056\/NEJMoa2111380","article-title":"Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma","volume":"386","author":"Doki","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1001\/jama.2021.12836","article-title":"Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients with Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial","volume":"326","author":"Luo","year":"2021","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/s41591-018-0136-1","article-title":"Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response","volume":"24","author":"Jiang","year":"2018","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41392-025-02311-x","article-title":"Mitochondrial metabolism and cancer therapeutic innovation","volume":"10","author":"Du","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zheng, W., Chen, C., Yu, J., Jin, C., and Han, T. (2021). An energy metabolism-based eight-gene signature correlates with the clinical outcome of esophagus carcinoma. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08030-0"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4118","DOI":"10.1016\/j.csbj.2023.08.022","article-title":"Mitochondrial energy metabolism correlates with an immunosuppressive tumor microenvironment and poor prognosis in esophageal squamous cell carcinoma","volume":"21","author":"Zhang","year":"2023","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9649","DOI":"10.18632\/aging.205892","article-title":"A novel mitochondrial metabolism-related gene signature for predicting the prognosis of oesophageal squamous cell carcinoma","volume":"16","author":"Lin","year":"2024","journal-title":"Aging"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Schiffmann, L.M., Plum, P.S., Fuchs, H.F., Babic, B., Bruns, C.J., and Schmidt, T. (2021). Tumor Microenvironment of Esophageal Cancer. Cancers, 13.","DOI":"10.3390\/cancers13184678"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5857","DOI":"10.2147\/CMAR.S258215","article-title":"Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche","volume":"12","author":"Han","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12943-023-01744-8","article-title":"Extracellular matrix remodeling in tumor progression and immune escape: From mechanisms to treatments","volume":"22","author":"Yuan","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, H., Shi, Q., Yang, Z., Wang, K., Zhang, Z., Huang, Z., Cui, X., and Li, F. (2021). An Extracellular Matrix-Based Signature Associated with Immune Microenvironment Predicts the Prognosis and Therapeutic Responses of Patients with Oesophageal Squamous Cell Carcinoma. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.598427"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.2147\/CMAR.S160186","article-title":"INHBA upregulation correlates with poorer prognosis in patients with esophageal squamous cell carcinoma","volume":"10","author":"Lyu","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4681","DOI":"10.1080\/21655979.2021.1957754","article-title":"Inhibin \u03b2-A (INHBA) induces epithelial-mesenchymal transition and accelerates the motility of breast cancer cells by activating the TGF-\u03b2 signaling pathway","volume":"12","author":"Yu","year":"2021","journal-title":"Bioengineered"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15007","DOI":"10.1038\/npjbcancer.2015.7","article-title":"Activin-A signaling promotes epithelial-mesenchymal transition, invasion, and metastatic growth of breast cancer","volume":"1","author":"Bashir","year":"2015","journal-title":"NPJ Breast Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.ymthe.2021.01.002","article-title":"TGFB1\/INHBA Homodimer\/Nodal-SMAD2\/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment","volume":"29","author":"Pauklin","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Loh, C.Y., Chai, J.Y., Tang, T.F., Wong, W.F., Sethi, G., Shanmugam, M.K., Chong, P.P., and Looi, C.Y. (2019). The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges. Cells, 8.","DOI":"10.3390\/cells8101118"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s12272-021-01321-x","article-title":"The role of epithelial-mesenchymal transition-regulating transcription factors in anti-cancer drug resistance","volume":"44","author":"Seo","year":"2021","journal-title":"Arch. Pharm. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Meng, C., Sun, Y., and Liu, G. (2023). Establishment of a prognostic model for ovarian cancer based on mitochondrial metabolism-related genes. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1144430"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5891","DOI":"10.1088\/0031-9155\/60\/15\/5891","article-title":"Monte Carlo simulation of a prototypical patient dosimetry system for fluoroscopic procedures","volume":"60","author":"Goertz","year":"2015","journal-title":"Phys. Med. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1245\/s10434-007-9631-1","article-title":"Activin a causes cancer cell aggressiveness in esophageal squamous cell carcinoma cells","volume":"15","author":"Yoshinaga","year":"2008","journal-title":"Ann. Surg. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1111\/j.1442-2050.2008.00928.x","article-title":"Overexpression of MMP-2 and MMP-9 in esophageal squamous cell carcinoma","volume":"22","author":"Li","year":"2009","journal-title":"Dis. Esophagus"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1186\/s13046-019-1384-8","article-title":"Hypoxic exosomes facilitate angiogenesis and metastasis in esophageal squamous cell carcinoma through altering the phenotype and transcriptome of endothelial cells","volume":"38","author":"Mao","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6268","DOI":"10.1038\/s41467-020-20019-0","article-title":"Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment","volume":"11","author":"Zheng","year":"2020","journal-title":"Nat. Commun."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1367\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T08:59:40Z","timestamp":1790067580000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1367"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":29,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["biom16091367"],"URL":"https:\/\/doi.org\/10.3390\/biom16091367","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}