International journal of reproductive biomedicine · 2026
A novel hsa_circ_0070963/miR-223-3p/ CCDC96-CCDC112 regulatory axis as a non-invasive biomarker for predicting sperm retrieval outcomes in non-obstructive azoospermia: A case-control study.
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Babakhanzadeh Emad, Khodadadian Ali, Nazari Majid, Mozhdeh Mahya, Fazeli Javad, Vahidi Serajoddin, Jafari Mohammad Hassan, Dehghani Mohammadreza, Ghafouri-Fard Soudeh, Ghasemi Nasrin
Аннотация
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.
OBJECTIVE: This study investigated the competing endogenous RNA regulatory axis hsa_circ_0070963/miR-223-3p/CCDC96-CCDC112 as a potential biomarker for predicting microsurgical testicular sperm extraction (micro-TESE) outcomes in NOA individuals.
MATERIALS 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⁺ (successful retrieval) and NOA⁻ (failed retrieval). Plasma RNA was extracted, and expression levels of candidate genes were measured by quantitative reverse transcription polymerase chain reaction.
RESULTS: Findings demonstrated significant downregulation of CCDC96 and CCDC112 in NOA plasma, particularly in NOA⁻ individuals, while hsa-miR-223-3p was upregulated, with the highest expression in NOA⁻ cases. Conversely, hsa_circ_0070963 was markedly reduced in NOA, especially in NOA⁻ 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.
CONCLUSION: hsa_circ_0070963/miR-223-3p/CCDC96-CCDC112 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.
OBJECTIVE: This study investigated the competing endogenous RNA regulatory axis hsa_circ_0070963/miR-223-3p/CCDC96-CCDC112 as a potential biomarker for predicting microsurgical testicular sperm extraction (micro-TESE) outcomes in NOA individuals.
MATERIALS 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⁺ (successful retrieval) and NOA⁻ (failed retrieval). Plasma RNA was extracted, and expression levels of candidate genes were measured by quantitative reverse transcription polymerase chain reaction.
RESULTS: Findings demonstrated significant downregulation of CCDC96 and CCDC112 in NOA plasma, particularly in NOA⁻ individuals, while hsa-miR-223-3p was upregulated, with the highest expression in NOA⁻ cases. Conversely, hsa_circ_0070963 was markedly reduced in NOA, especially in NOA⁻ 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.
CONCLUSION: hsa_circ_0070963/miR-223-3p/CCDC96-CCDC112 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.