{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T11:06:24Z","timestamp":1779015984733,"version":"3.51.4"},"reference-count":22,"publisher":"Knowledge E DMCC","issue":"3","license":[{"start":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T00:00:00Z","timestamp":1778976000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":["knepublishing.com"],"crossmark-restriction":true},"short-container-title":["IJRM"],"abstract":"<jats:p>Background: Non-obstructive azoospermia (NOA) is a severe cause of male infertility. Testicular sperm extraction has limited success, largely due to the absence of reliable, non-invasive biomarkers to predict outcomes. Emerging evidence highlights the role of non-coding RNAs in spermatogenesis, providing promising targets for biomarker development.\r\nObjective: This study investigated the competing endogenous RNA regulatory axis hsa_circ_0070963\/miR-223-3p\/CCDC96\u2013CCDC112 as a potential biomarker for predicting microsurgical testicular sperm extraction (micro-TESE) outcomes in NOA individuals.\r\nMaterials and Methods: In this case-control study, 60 men with NOA undergoing micro-TESE and 40 fertile controls were recruited. Testicular histology categorized individuals into Sertoli cell-only syndrome, hypospermatogenesis, or maturation arrest. Individuals were further stratified into NOA\u207a (successful retrieval) and NOA\u207b (failed retrieval). Plasma RNA was extracted, and expression levels of candidate genes were measured by quantitative reverse transcription polymerase chain reaction.\r\nResults: Findings demonstrated significant downregulation of CCDC96 and CCDC112 in NOA plasma, particularly in NOA\u207b individuals, while hsa-miR-223-3p was upregulated, with the highest expression in NOA\u207b cases. Conversely, hsa_circ_0070963 was markedly reduced in NOA, especially in NOA\u207b individuals. Dysregulation was more pronounced in hypospermatogenesis and maturation arrest compared to Sertoli cell-only syndrome. Receiver operating characteristic analysis revealed strong predictive accuracy, with hsa_circ_0070963 (area under the receiver operating characteristic curve = 0.983) and hsa-miR-223-3p (area under the curve = 0.970) outperforming CCDC96 and CCDC112.\r\nConclusion: The hsa_circ_0070963\/miR-223-3p\/CCDC96\u2013CCDC112 axis represents a novel competing endogenous RNAs regulatory network linked to impaired spermatogenesis. Its expression profile provides mechanistic insights and serves as a robust, non-invasive biomarker for predicting micro-TESE outcomes, supporting improved stratification and individualized treatment strategies in male infertility.<\/jats:p>","DOI":"10.18502\/ijrm.v24i3.21113","type":"journal-article","created":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T09:49:51Z","timestamp":1779011391000},"update-policy":"https:\/\/doi.org\/10.18502\/knecrossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["A novel hsa_circ_0070963\/miR-223-3p\/ CCDC96\u2013CCDC112 regulatory axis as a non-invasive biomarker for predicting sperm retrieval outcomes in non-obstructive azoospermia: A case-control study"],"prefix":"10.18502","volume":"24","author":[{"given":"Emad","family":"Babakhanzadeh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Khodadadian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Majid","family":"Nazari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahya","family":"Mozhdeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javad","family":"Fazeli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serajoddin","family":"Vahidi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Hassan","family":"Jafari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammadreza","family":"Dehghani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soudeh","family":"Ghafouri-Fard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nasrin","family":"Ghasemi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"7770","published-online":{"date-parts":[[2026,5,17]]},"reference":[{"key":"331362","doi-asserted-by":"crossref","unstructured":"[1] Tharakan T, Luo R, Jayasena ChN, Minhas S. 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Prevalence and clinical implications of biochemical hypogonadism in patients with nonobstructive azoospermia undergoing infertility evaluation. F S Rep 2024; 5: 14\u201322.","DOI":"10.1016\/j.xfre.2023.11.007"},{"key":"331367","doi-asserted-by":"crossref","unstructured":"[6] Achermann AP, Pereira TA, Esteves SC. Microdissection testicular sperm extraction (micro-TESE) in men with infertility due to nonobstructive azoospermia: Summary of current literature. Int Urol Nephrol 2021; 53: 2193\u20132210.","DOI":"10.1007\/s11255-021-02979-4"},{"key":"331368","doi-asserted-by":"crossref","unstructured":"[7] Kaltsas A, Stavros S, Kratiras Z, Zikopoulos A, Machairiotis N, Potiris A, et al. Predictors of successful testicular sperm extraction: A new era for men with non-obstructive azoospermia. Biomedicines 2024; 12: 2679.","DOI":"10.3390\/biomedicines12122679"},{"key":"331369","doi-asserted-by":"crossref","unstructured":"[8] Shi Sh, Wang T, Wang L, Wang M. 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Circular RNAs and their role in male infertility: A systematic review. Biomolecules 2023; 13: 1046.","DOI":"10.3390\/biom13071046"},{"key":"331373","doi-asserted-by":"crossref","unstructured":"[12] Liu Z, Li X, Yang X, Zhang B, Chen D, Yuan Y, et al. Identification of biomarkers of male infertility through the circRNA expression profiling of seminal plasma. J Biomed Res 2025; 39: 367.","DOI":"10.7555\/JBR.38.20240192"},{"key":"331374","doi-asserted-by":"crossref","unstructured":"[13] Lv MQ, Yang YQ, Li YX, Zhou L, Ge P, Sun RF, et al. A detection model of testis-derived circular RNAs in serum for predicting testicular sperm retrieval rate in non-obstructive azoospermia patients. Andrology 2024; 12: 1751\u20131763.","DOI":"10.1111\/andr.13617"},{"key":"331375","doi-asserted-by":"crossref","unstructured":"[14] Song Q, Liu J, Li C, Liu R, Zhang N, Shi H. Prognostic value of miR-223 for pregnancy outcomes in patients with in vitro fertilisation and intracytoplasmic sperm injection. 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Int J Oncol 2016; 50: 356\u2013364.","DOI":"10.3892\/ijo.2016.3807"},{"key":"331382","doi-asserted-by":"crossref","unstructured":"[21] Attia H, Finocchi F, Orciani M, Mehdi M, Zidi Jrah I, Lazzarini R, et al. Pro-inflammatory cytokines and microRNAs in male infertility. Mol Biol Rep 2021; 48: 5935\u20135942.","DOI":"10.1007\/s11033-021-06593-6"},{"key":"331383","doi-asserted-by":"crossref","unstructured":"[22] Ji D, Chen G-F, Wang J-C, Ji S-H, Wu X-W, Lu X-J, et al. Hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3. 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