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Here, we developed an integrated strategy combining protoplast\u2010based strain evolution, medium optimization, and transcriptomic analysis to enhance adenosine biosynthesis in\n                    <jats:italic>P. hepiali<\/jats:italic>\n                    . Efficient protoplast preparation was achieved using 48\u2009h seed cultures digested with 1% driselase and 1% yatalase at 28\u00b0C for 7\u2009h, and 40\u2009s ultraviolet irradiation was selected for mutant library construction. A stable mutant,\n                    <jats:italic>P. hepiali<\/jats:italic>\n                    A3, produced 65.32\u2009mg\/L adenosine, representing a 31.62% increase over the parental strain. Subsequent response surface optimization identified maltose, peptone, and aspartic acid as key nutritional factors, increasing the adenosine titer to 170.41\u2009mg\/L in shake flasks and 191.36\u2009mg\/L in a 5\u2010L bioreactor. Comparative transcriptomic analysis revealed extensive metabolic remodeling involving central carbon metabolism, ribose precursor supply, purine nucleotide metabolism, and sterol biosynthesis. Upregulation of ribose\u20105\u2010phosphate isomerase\n                    <jats:italic>RPIB<\/jats:italic>\n                    and downregulation of\n                    <jats:italic>ADA<\/jats:italic>\n                    related to purine degradation were associated with enhanced purine nucleoside accumulation. These results provide transcriptomic insights into adenosine biosynthesis and establish a practical framework for improving fungal nucleoside cell factories.\n                  <\/jats:p>","DOI":"10.1002\/bit.70365","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:46:31Z","timestamp":1788155191000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhanced Adenosine Biosynthesis in\n                    <i>Paecilomyces hepiali<\/i>\n                    Through Strain Evolution and Transcriptomic Insights"],"prefix":"10.1002","author":[{"given":"Ai\u2010Ping","family":"Pang","sequence":"first","affiliation":[{"name":"Huadong Industry Technology Institute of Synthetic Biology Zhejiang University of Technology Hangzhou Zhejiang the People's Republic of China"},{"name":"National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals Zhejiang University of Technology Hangzhou the People's Republic of China"},{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering Zhejiang University of Technology Hangzhou the People's Republic of China"},{"name":"Zhejiang Key Laboratory of Functional Structural Lipid Synthesis and Application Hangzhou Zhejiang the People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals Zhejiang University of Technology Hangzhou the People's Republic of China"},{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering Zhejiang University of Technology Hangzhou the People's Republic of 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