Integrated analysis of autophagy-related lncRNAs and oxidative DNA damage reveals molecular signatures of severe sperm abnormalities.

PURPOSE: Autophagy is a critical intracellular degradation pathway involved in cellular homeostasis and spermatogenesis. Long noncoding RNAs (lncRNAs) regulate autophagy-related signaling; however, their role in male infertility remains unclear. This study aimed to evaluate the association between autophagy-related lncRNAs, oxidative DNA damage, and sperm abnormalities in infertile men.

METHODS

A total of 120 men were included: 30 fertile controls, 30 with asthenospermia (AS), 30 with teratospermia (TS), and 30 with oligoasthenoteratozoospermia (OATS). Expression levels of autophagy-related lncRNAs and protein-coding genes were quantified using real-time PCR. LC3 protein expression was assessed by Western blot, and sperm 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were measured by ELISA. Statistical analyses included ANOVA, correlation analysis, and receiver operating characteristic (ROC) curve analysis.

RESULTS

Autophagy-related lncRNAs (H19, HOTAIR, MALAT1, NBR2, HULC, and ROR) and key autophagy markers (ATG7 and LC3) were significantly upregulated predominantly in the OATS group compared with controls and other groups (p < 0.05). LC3 protein levels were also significantly increased in OATS. Sperm 8-OHdG levels were significantly elevated in both AS and OATS groups. Correlation analyses revealed significant associations between hormone levels (FSH, LH, and prolactin) and lncRNA expression, particularly in the OATS group. ROC analysis demonstrated moderate discrimination for OATS versus other groups (AUC = 0.754) and excellent discrimination for OATS versus controls (AUC = 0.902).

CONCLUSION

Dysregulation of autophagy-related lncRNAs and increased oxidative DNA damage are strongly associated with severe sperm abnormalities. The observed molecular alterations may represent either contributors to sperm dysfunction or adaptive responses to oxidative stress. Combined evaluation of these markers showed promising discriminatory performance, although validation in larger independent cohorts is required before clinical application.