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However, repeated lactation and advancing parity impose cumulative metabolic and inflammatory stress that often compromises fertility and shortens productive lifespan. Increasing evidence suggests that immune dysregulation contributes to parity\u2010associated reproductive decline, raising the possibility that sustained milk production requires adaptive immune regulation. We hypothesized that cows achieving reproductive longevity exhibit parity\u2010dependent immune remodeling that supports continued reproductive function and extended milk production. To test this hypothesis, we profiled blood transcriptomes from 131 Holstein cows spanning parities 1\u20139. Analysis of 17\u2009422 expressed genes identified six distinct parity\u2010associated expression trajectories, revealing coordinated transcriptomic remodeling with increasing reproductive history. Differential expression analysis identified 1 405 parity\u2010associated genes enriched in immune\u2010 and stress\u2010related pathways, including MAPK and Rap1 signaling. Weighted gene co\u2010expression network analysis further identified immune\u2010regulatory modules strongly correlated with parity and key reproductive indicators, suggesting a central role of immune adaptation in sustaining reproductive efficiency. Machine learning analysis of 256 genes in significantly enriched pathways with P\u2010adjusted &lt;\u20090.05 prioritized PDE4C, APLN, and CDH15 as potential key predictors of reproductive persistence. Integration with co\u2010expression networks demonstrated that these genes may function as highly connected hub nodes within immune\u2010 and stress\u2010responsive modules. Collectively, these results indicate that coordinated immune signaling networks are associated with reproductive persistence and thereby contribute to extended milk production in dairy cows. This study provides molecular insight into the immune mechanisms underlying productive longevity and identifies candidate biomarkers with potential applications in genomic selection and precision herd management.<\/jats:p>","DOI":"10.1096\/fj.202600488rr","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T10:54:18Z","timestamp":1780138458000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune\u2010Adaptive Transcriptomic Networks Supporting Sustained Milk Production and Reproductive Longevity in Dairy Cows"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8560-7801","authenticated-orcid":false,"given":"Zhenjiang","family":"An","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology Nanjing Agricultural University  Nanjing China"},{"name":"Institute of Animal Science Jiangsu Academy of Agricultural Sciences  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