{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T01:57:05Z","timestamp":1783475825508,"version":"3.55.0"},"reference-count":82,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shenzhen Medical Research Fund","award":["B2404004"],"award-info":[{"award-number":["B2404004"]}]},{"name":"Guangzhou Basic Research Plan of Basic and Applied Basic Research Foundation","award":["2024A04J3925"],"award-info":[{"award-number":["2024A04J3925"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32470641"],"award-info":[{"award-number":["32470641"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970572"],"award-info":[{"award-number":["81970572"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2022A1515012576"],"award-info":[{"award-number":["2022A1515012576"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2025A1515011182"],"award-info":[{"award-number":["2025A1515011182"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Research Fund for Clinical Doctors of Guangzhou Women and Children\u2019s Medical Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cryptorchidism, characterized by undescended testes, is associated with infertility and increased cancer risk through complex, multifactorial pathophysiological mechanisms involving interconnected alterations in testicular microenvironment, including but not limited to elevated temperature, hormonal dysregulation, altered vascular perfusion, and immune responses. These factors interact synergistically to drive testicular pathology. Using a surgically induced bilateral cryptorchid mouse model established at postnatal day 21 (PND21), we investigated phase-specific pathological mechanisms through analyses at prepubertal (PND35) and sexually mature (PND70) phases. Our transcriptome analysis revealed distinct molecular signatures at different developmental phases, with prepubertal cryptorchid testes showing 2570 differentially expressed genes predominantly enriched in immunoproteasome components and inflammatory pathways, while sexually mature testes exhibited 883 differentially expressed genes primarily related to extracellular matrix (ECM) remodeling and oncogenic pathways. Prepubertal molecular changes indicated immunoproteasome activation and inflammatory responses, whereas mature-phase alterations were characterized by ECM reorganization and fibrotic remodeling. Functional analysis demonstrated prepubertal enrichment in spermatogenesis regulation and interferon responses, while mature-phase signatures were associated with apoptosis, epithelial\u2013mesenchymal transition, and inflammatory signaling cascades. Phase-specific oncogenic pathway correlations revealed distinct mechanisms: metabolic reprogramming and epigenetic regulation in prepubertal testes versus structural remodeling and invasion-related pathways in mature testes. Molecular validation confirmed elevated PI3K-Akt and NF-\u03baB signaling at both developmental phases, identifying these as potential therapeutic targets. This first phase-resolved characterization of cryptorchidism pathology provides insights into developmental phase-specific mechanisms and suggests timing-dependent therapeutic strategies. Although differing from human congenital cryptorchidism in developmental timing and etiology, our surgically induced model recapitulates anatomical testicular malposition with multiple inseparable pathophysiological alterations, and the identified molecular signatures reflect integrated responses to the complex cryptorchid microenvironment.<\/jats:p>","DOI":"10.3390\/biom15111584","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T10:56:27Z","timestamp":1762858587000},"page":"1584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Developmental Phase-Specific Molecular Signatures and Signaling Pathways in Cryptorchidism-Induced Testicular Damage"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3821-8390","authenticated-orcid":false,"given":"Xinying","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4497-6297","authenticated-orcid":false,"given":"Fuming","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1361-4987","authenticated-orcid":false,"given":"Yijing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaonan","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8350-8648","authenticated-orcid":false,"given":"Dian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-0518","authenticated-orcid":false,"given":"Xiangliang","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1957-7197","authenticated-orcid":false,"given":"Hongkun","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9632-6886","authenticated-orcid":false,"given":"Qianlong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1459-5680","authenticated-orcid":false,"given":"Wen","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9951-9563","authenticated-orcid":false,"given":"Guochang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6662-5837","authenticated-orcid":false,"given":"Zhongzhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8265-2023","authenticated-orcid":false,"given":"Tianxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Urology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"149746","DOI":"10.1016\/j.scitotenv.2021.149746","article-title":"Anti-androgenic compounds in breast milk and cryptorchidism among Norwegian boys in the HUMIS birth cohort","volume":"803","author":"Collet","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.jpedsurg.2019.06.018","article-title":"Torsion of an undescended testis\u2014A surgical pediatric emergency","volume":"55","author":"Kargl","year":"2020","journal-title":"J. Pediatr. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1097\/JU.0000000000000615","article-title":"Fertility Potential is Compromised in 20% to 25% of Boys with Nonsyndromic Cryptorchidism despite Orchiopexy within the First Year of Life","volume":"203","author":"Hildorf","year":"2020","journal-title":"J. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101709","DOI":"10.1016\/j.xcrm.2024.101709","article-title":"Decoding the pathogenesis of spermatogenic failure in cryptorchidism through single-cell transcriptomic profiling","volume":"5","author":"Wang","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.jpurol.2024.07.015","article-title":"Two-stage orchiopexy for intra-abdominal testis with short spermatic vessels wrapped in anti-adhesion conduit. 25 years of experience","volume":"20","author":"Dessanti","year":"2024","journal-title":"J. Pediatr. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.jpurol.2022.10.031","article-title":"The positive predictive value of using fsh and Inhibin-B serum levels to diagnose gonadotropin insufficiency in bilateral cryptorchid boys is high","volume":"18","author":"Hildorf","year":"2022","journal-title":"J. Pediatr. Urol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1111\/brv.12921","article-title":"Testicular heat stress, a historical perspective and two postulates for why male germ cells are heat sensitive","volume":"98","author":"Robinson","year":"2023","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e12819","DOI":"10.1111\/jpi.12819","article-title":"Melatonin alleviates the heat stress-induced impairment of Sertoli cells by reprogramming glucose metabolism","volume":"73","author":"Deng","year":"2022","journal-title":"J. Pineal Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1093\/biolre\/ioaa225","article-title":"The IL-27 component EBI-3 and its receptor subunit IL-27R\u03b1 are essential for the cytoprotective action of humanin on male germ cells","volume":"104","author":"Jia","year":"2021","journal-title":"Biol. Reprod."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3906","DOI":"10.1097\/MS9.0000000000000976","article-title":"Investigating the effect of sudden occlusion of the testicular vessels on the testicular tissue in rat models","volume":"85","author":"Shojaeian","year":"2023","journal-title":"Ann. Med. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1007\/s43032-023-01430-6","article-title":"Joint Analysis of Genome-wide DNA Methylation and Transcription Sequencing Identifies the Role of BAX Gene in Heat Stress-Induced-Sertoli Cells Apoptosis","volume":"31","author":"Hu","year":"2024","journal-title":"Reprod. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, D., Hildorf, S., Ntemou, E., Dong, L., Pors, S.E., Mamsen, L.S., Fedder, J., Hoffmann, E.R., Clasen-Linde, E., and Cortes, D. (2022). Characterization and Survival of Human Infant Testicular Cells After Direct Xenotransplantation. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.853482"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1111\/jcmm.17837","article-title":"Environmental oestrogens disrupt testicular descent and damage male reproductive health: Mechanistic insight","volume":"27","author":"Li","year":"2023","journal-title":"J. Cell. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.jpedsurg.2013.02.001","article-title":"Undescended testis: The underlying mechanisms and the effects on germ cells that cause infertility and cancer","volume":"48","author":"Hutson","year":"2013","journal-title":"J. Pediatr. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1056\/NEJMra1407550","article-title":"Testicular cancer\u2014discoveries and updates","volume":"371","author":"Hanna","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"hoaf021","DOI":"10.1093\/hropen\/hoaf021","article-title":"Pre-existing morbidity pattern in a Danish testicular cancer cohort: Insights beyond the testicular dysgenesis syndrome hypothesis","volume":"2025","author":"Ornstrup","year":"2025","journal-title":"Hum. Reprod. Open"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1097\/JU.0000000000001896","article-title":"Testicular Temperature and the Effects of Orchiopexy in Infants with Cryptorchidism","volume":"206","author":"Shiraishi","year":"2021","journal-title":"J. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1097\/JU.0000000000002345","article-title":"Malignancy Yield of Testis Pathology in Older Boys and Adolescents with Cryptorchidism","volume":"207","author":"Xu","year":"2022","journal-title":"J. Urol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1016\/j.gendis.2021.03.006","article-title":"Retinoic acid can improve autophagy through depression of the PI3K-Akt-mTOR signaling pathway via RAR\u03b1 to restore spermatogenesis in cryptorchid infertile rats","volume":"9","author":"Long","year":"2022","journal-title":"Genes Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"108704","DOI":"10.1016\/j.reprotox.2024.108704","article-title":"Expression and localization of Cyclin D1\/Nanog and NF-\u03baB\/Bax protein in dysplastic testicles of mice","volume":"130","author":"Liu","year":"2024","journal-title":"Reprod. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/iep.12384","article-title":"Time response of rat testicular alterations induced by cryptorchidism and orchiopexy","volume":"102","author":"Gomide","year":"2021","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/s41390-021-01458-x","article-title":"BDNF is upregulated by androgen in the inguinal fat pad of immature mice and may regulate inguinoscrotal testicular descent","volume":"91","author":"Vikraman","year":"2022","journal-title":"Pediatr. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1369\/0022155421991629","article-title":"Cellular Expression and Subcellular Localization of Wwox Protein During Testicular Development and Spermatogenesis in Rats","volume":"69","author":"Mahmud","year":"2021","journal-title":"J. Histochem. Cytochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127547","DOI":"10.1016\/j.jhazmat.2021.127547","article-title":"Prenatal exposure to environmentally relevant levels of PBDE-99 leads to testicular dysgenesis with steroidogenesis disorders","volume":"424","author":"Zhao","year":"2022","journal-title":"J. Hazard. Mater."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.cell.2012.06.045","article-title":"Small-molecule inhibition of BRDT for male contraception","volume":"150","author":"Matzuk","year":"2012","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"144059","DOI":"10.1016\/j.scitotenv.2020.144059","article-title":"Bisphenol S perturbs Sertoli cell junctions in male rats via alterations in cytoskeletal organization mediated by an imbalance between mTORC1 and mTORC2","volume":"762","author":"Wu","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1002\/tox.22559","article-title":"Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity through Nrf2-mediated Notch1 signaling pathway in Sprague-Dawley rats","volume":"33","author":"Tang","year":"2018","journal-title":"Environ. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1021\/acs.jproteome.8b00702","article-title":"Cytoscape StringApp: Network Analysis and Visualization of Proteomics Data","volume":"18","author":"Doncheva","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bruggeman, J.W., Irie, N., Lodder, P., van Pelt, A.M.M., Koster, J., and Hamer, G. (2020). Tumors Widely Express Hundreds of Embryonic Germline Genes. Cancers, 12.","DOI":"10.1101\/2020.09.08.287284"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1111\/andr.12923","article-title":"The role of miR-128-3p through MAPK14 activation in the apoptosis of GC2 spermatocyte cell line following heat stress","volume":"9","author":"Zou","year":"2021","journal-title":"Andrology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1111\/andr.13381","article-title":"Exposure to elevated temperature affects the expression of PIWI-interacting RNAs and associated transcripts in mouse testes","volume":"11","author":"Chen","year":"2023","journal-title":"Andrology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1159\/000521649","article-title":"GABAB Receptor Antagonism from Birth to Weaning Permanently Modifies Kiss1 Expression in the Hypothalamus and Gonads in Mice","volume":"112","author":"Libertun","year":"2022","journal-title":"Neuroendocrinology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13918","DOI":"10.4081\/aiua.2025.13918","article-title":"Does bilateral undescended testis have worst testicular function than unilateral cases? A meta-analysis of adult orchidopexy patients","volume":"97","author":"Adnyana","year":"2025","journal-title":"Arch. Ital. Urol. Androl."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.jpurol.2020.09.002","article-title":"The incidence of epididymal anomalies in the bilateral and unilateral cryptorchidism cases: A comparative study","volume":"16","author":"Cinislioglu","year":"2020","journal-title":"J. Pediatr. Urol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kowalska, M., Tylicka, M., Koper-Lenkiewicz, O.M., Kami\u0144ska, J., Dorf, J., and Matuszczak, E. (2025). Plasma concentration of MMP-17 is elevated in boys with cryptorchidism and correlates with HSP-70. Sci. Rep., 15.","DOI":"10.1038\/s41598-024-84214-5"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"dev201093","DOI":"10.1242\/dev.201093","article-title":"Loss of WNT4 in the gubernaculum causes unilateral cryptorchidism and fertility defects","volume":"149","author":"Seth","year":"2022","journal-title":"Development"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1159\/000323955","article-title":"Testicular gene expression in cryptorchid boys at risk of azoospermia","volume":"5","author":"Hadziselimovic","year":"2011","journal-title":"Sex. Dev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.gendis.2018.11.002","article-title":"Bioinformatic identification of key genes and molecular pathways in the spermatogenic process of cryptorchidism","volume":"6","author":"Zhou","year":"2019","journal-title":"Genes Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/ptr.6801","article-title":"Saponins derived from the stems and leaves of Panax ginseng attenuate scrotal heat-induced spermatogenic damage via inhibiting the MAPK mediated oxidative stress and apoptosis in mice","volume":"35","author":"Liu","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Basler, M., and Groettrup, M. (2021). On the Role of the Immunoproteasome in Protein Homeostasis. Cells, 10.","DOI":"10.3390\/cells10113216"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6786","DOI":"10.1111\/jcmm.16682","article-title":"Immunoproteasome impairment via \u03b25i\/LMP7-deletion leads to sustained pancreatic injury from experimental pancreatitis","volume":"25","author":"Ebstein","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kriger, D., Podenkova, U.I., Bakhmet, E.I., Potapenko, E., Ivanova, E., Tomilin, A.N., and Tsimokha, A.S. (2024). Evidence of Immunoproteasome Expression Onset in the Formative State of Pluripotency in Mouse Cells. Cells, 13.","DOI":"10.3390\/cells13161362"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"77047","DOI":"10.1007\/s11356-022-21134-9","article-title":"The inhibition of CFTR in the descended testis of SD rats with unilateral cryptorchidism induced by di-(2-ethylhexyl) phthalate (DEHP)","volume":"29","author":"Tang","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1158\/1535-7163.MCT-23-0931","article-title":"Immunoproteasome Activation Expands the MHC Class I Immunopeptidome, Unmasks Neoantigens, and Enhances T-cell Anti-Myeloma Activity","volume":"23","author":"Rana","year":"2024","journal-title":"Mol. Cancer Ther."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, M., Tong, W., Dai, C., Lu, G., Jin, D., and Deng, F. (2025). Downregulation of the immunoproteasome subunit PSMB8 attenuates sepsis-associated acute kidney injury through the NF-\u03baB pathway. Immunobiology, 230.","DOI":"10.1016\/j.imbio.2024.152862"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"121729","DOI":"10.1016\/j.envpol.2023.121729","article-title":"Aflatoxin B1 disrupts testicular development via the cell cycle-related Ras\/PI3K\/Akt signaling in mice and pig","volume":"329","author":"Zhang","year":"2023","journal-title":"Environ. Pollut."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.theriogenology.2024.03.003","article-title":"Heme oxygenase 1 (HO1) regulates autophagy and apoptosis via the PI3K\/AKT\/mTOR signaling pathway of yak Sertoli cells","volume":"220","author":"Yan","year":"2024","journal-title":"Theriogenology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.21037\/tp-21-31","article-title":"AKT3 and related molecules as potential biomarkers responsible for cryptorchidism and cryptorchidism-induced azoospermia","volume":"10","author":"Jia","year":"2021","journal-title":"Transl. Pediatr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/andr.12444","article-title":"Effects of the insulin-like growth factor system on testicular differentiation and function: A review of the literature","volume":"6","author":"Cannarella","year":"2018","journal-title":"Andrology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e240177","DOI":"10.1530\/REP-24-0177","article-title":"Role of L-glutamine in the regulation of rat Sertoli cell proliferation by FSH","volume":"168","author":"Centola","year":"2024","journal-title":"Reproduction"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"15804","DOI":"10.1021\/acs.jafc.2c06377","article-title":"Ginsenoside Rk1 Prevents UVB Irradiation-Mediated Oxidative Stress, Inflammatory Response, and Collagen Degradation via the PI3K\/AKT\/NF-\u03baB Pathway In Vitro and In Vivo","volume":"70","author":"Liu","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"108845","DOI":"10.1016\/j.reprotox.2025.108845","article-title":"Chronic unpredictable stress exposure disrupts testicular function by modulating germ cell-junctional dynamics and Nrf2\/HO-1\/IKK\u03b2\/NF-\u03baB pathway","volume":"132","author":"Yadav","year":"2025","journal-title":"Reprod. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s12272-023-01426-5","article-title":"MEKs\/ERKs-mediated FBXO1\/E2Fs interaction interference modulates G(1)\/S cell cycle transition and cancer cell proliferation","volume":"46","author":"Lee","year":"2023","journal-title":"Arch. Pharm. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"eadg3840","DOI":"10.1126\/scitranslmed.adg3840","article-title":"The extracellular matrix as hallmark of cancer and metastasis: From biomechanics to therapeutic targets","volume":"16","author":"Sleeboom","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Xiao, L., Wang, Z., Lu, N., Wei, H., Kang, J., Yuan, M., Sheng, X., Qi, X., Xing, K., and Guo, Y. (2022). Dihydrotestosterone through blockade of TGF-\u03b2\/Smad signaling mediates the anti-fibrosis effect under hypoxia in canine Sertoli cells. J. Steroid Biochem. Mol. Biol., 216.","DOI":"10.1016\/j.jsbmb.2021.106041"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Hutson, J.M., Li, R., Southwell, B.R., Petersen, B.L., Thorup, J., and Cortes, D. (2012). Germ cell development in the postnatal testis: The key to prevent malignancy in cryptorchidism?. Front. Endocrinol., 3.","DOI":"10.3389\/fendo.2012.00176"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1111\/and.12139","article-title":"Prevalence of carcinoma in situ in testicular biopsies of infertile Iranian men","volume":"46","author":"Soltanghoraee","year":"2014","journal-title":"Andrologia"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Serrano, J.J., and Medina, M. (2025). Metabolic Reprogramming at the Edge of Redox: Connections Between Metabolic Reprogramming and Cancer Redox State. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020498"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/bs.ircmb.2022.08.001","article-title":"Targeting amino acid metabolism in cancer","volume":"373","author":"Safrhansova","year":"2022","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"111425","DOI":"10.1016\/j.cellsig.2024.111425","article-title":"TAF1D promotes tumorigenesis and metastasis by activating PI3K\/AKT\/mTOR signaling in clear cell renal cell carcinoma","volume":"124","author":"Hu","year":"2024","journal-title":"Cell. Signal."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Andrade, F., Vigueras-Villase\u00f1or, R.M., Ch\u00e1vez-Salda\u00f1a, M.D., Rojas-Casta\u00f1eda, J.C., Bahena-Ocampo, I.U., Ar\u00e9chaga-Ocampo, E., Flores-Fortis, M., D\u00edaz-Ch\u00e1vez, J., Herrera, L.A., and Landero-Huerta, D.A. (2023). Molecular Characterization of Patients with Cryptorchidism: Preliminary Search for an Expression Profile Related to That of Testicular Germ-Cell Tumors. Diagnostics, 13.","DOI":"10.3390\/diagnostics13183020"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1111\/andr.13397","article-title":"Comparing the adult and pre-pubertal testis: Metabolic transitions and the change in the spermatogonial stem cell metabolic microenvironment","volume":"11","author":"Voigt","year":"2023","journal-title":"Andrology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.neo.2021.05.008","article-title":"On the origin of germ cell neoplasia in situ: Dedifferentiation of human adult Sertoli cells in cross talk with seminoma cells in vitro","volume":"23","author":"Fink","year":"2021","journal-title":"Neoplasia"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/PAP.0000000000000438","article-title":"Evolution of Testicular Germ Cell Tumors in the Molecular Era with Histogenetic Implications","volume":"31","author":"Kilic","year":"2024","journal-title":"Adv. Anat. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1080\/10520295.2020.1776393","article-title":"Investigation of EGFR\/pi3k\/Akt signaling pathway in seminomas","volume":"96","author":"Guerra","year":"2021","journal-title":"Biotech. Histochem."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Bossio, S., Perri, A., Malivindi, R., Giordano, F., Rago, V., Mirabelli, M., Salatino, A., Brunetti, A., Greco, E.A., and Aversa, A. (2022). Oleuropein Counteracts Both the Proliferation and Migration of Intra- and Extragonadal Seminoma Cells. Nutrients, 14.","DOI":"10.3390\/nu14112323"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s13287-024-03724-1","article-title":"NANOG controls testicular germ cell tumour stemness through regulation of MIR9-2","volume":"15","author":"Cardenas","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"100702","DOI":"10.1016\/j.modpat.2024.100702","article-title":"Molecular Diversity of Embryonic-Type Neuroectodermal Tumors Arising from Testicular Germ Cell Tumors","volume":"38","author":"Zong","year":"2025","journal-title":"Mod. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"155503","DOI":"10.1016\/j.phymed.2024.155503","article-title":"Natural products and derivatives in renal, urothelial and testicular cancers: Targeting signaling pathways and therapeutic potential","volume":"127","author":"Li","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1016\/j.cell.2024.03.027","article-title":"DrugMap: A quantitative pan-cancer analysis of cysteine ligandability","volume":"187","author":"Takahashi","year":"2024","journal-title":"Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/s41586-020-2682-1","article-title":"Cancer SLC43A2 alters T cell methionine metabolism and histone methylation","volume":"585","author":"Bian","year":"2020","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.eururo.2021.01.014","article-title":"Functional and Taxonomic Dysbiosis of the Gut, Urine, and Semen Microbiomes in Male Infertility","volume":"79","author":"Lundy","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.molcel.2024.01.014","article-title":"C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line","volume":"84","author":"Zoch","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s40164-024-00529-z","article-title":"Versatile function of NF-\u0138B in inflammation and cancer","volume":"13","author":"Ma","year":"2024","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1182\/bloodadvances.2020002417","article-title":"Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection","volume":"5","author":"Yoshimori","year":"2021","journal-title":"Blood Adv."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Sim\u00f3n, E., Lleix\u00e0, C., Suarez-Calvet, X., Diaz-Manera, J., Illa, I., Gallardo, E., and de Luna, N. (2020). Proteasome inhibitors reduce thrombospondin-1 release in human dysferlin-deficient myotubes. BMC Musculoskelet. Disord., 21.","DOI":"10.1186\/s12891-020-03756-7"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"White, M.J.V., Raczy, M.M., Budina, E., Yuba, E., Solanki, A., Shim, H.-N., Zhang, Z.J., Gray, L.T., Cao, S., and Alpar, A.T. (2025). Engineering IL-10 and rapamycin to bind collagen leads to improved anti fibrotic efficacy in lung and kidney fibrosis. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-94073-3"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.jpurol.2022.06.020","article-title":"The protective effect of curcumin on testicular tissue in a cryptorchid rat model","volume":"18","author":"Feng","year":"2022","journal-title":"J. Pediatr. Urol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.freeradbiomed.2025.02.043","article-title":"The ferroptosis of sertoli cells inducing blood-testis barrier damage is produced by oxidative stress in cryptorchidism","volume":"232","author":"Zeng","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"8462","DOI":"10.1038\/s41467-023-44305-9","article-title":"Single-cell multi-omics analysis of human testicular germ cell tumor reveals its molecular features and microenvironment","volume":"14","author":"Lu","year":"2023","journal-title":"Nat. Commun."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1584\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T05:28:02Z","timestamp":1763011682000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1584"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,11]]},"references-count":82,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["biom15111584"],"URL":"https:\/\/doi.org\/10.3390\/biom15111584","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,11]]}}}