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Notably, PART patients show a higher degree of tau hyperphosphorylation in the entorhinal cortex (EC) than AD, yet the molecular mechanisms driving A\u03b2\u2010independent tau hyperphosphorylation in PART remain poorly understood. Herein, through transcriptomic profiling of postmortem EC tissues and in vitro and in vivo functional validation, the present study identifies protein arginine methyltransferase 3 (PRMT3) as a critical driver of tau hyperphosphorylation. Mechanistically, PRMT3\u2010mediated tau hyperphosphorylation is dependent on asymmetric dimethylation of histone H4 at arginine 3 (H4R3me2a), which upregulates miR\u2010448. Elevated miR\u2010448 specifically targets and suppresses IGF1R, leading to downstream GSK3\u03b2 activation and subsequent tau hyperphosphorylation through PI3K\/AKT\/GSK3\u03b2 signaling. Treatment with SGC707, a selective PRMT3 inhibitor, effectively reduces tau hyperphosphorylation and demonstrates therapeutic promise for PART and potentially other tauopathies. Collectively, this study defines the PRMT3\/H4R3me2a\/miR\u2010448 axis as a critical regulatory pathway in tau hyperphosphorylation within PART, underscoring the potential of PRMT3 inhibition as a targeted therapeutic strategy for tauopathies.<\/jats:p>","DOI":"10.1002\/advs.202506044","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T02:44:25Z","timestamp":1746758665000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PRMT3\u2010Mediated H4R3me2a Promotes Primary Age\u2010Related Tauopathy by Driving Tau Hyperphosphorylation in Neuron"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8550-7641","authenticated-orcid":false,"given":"Haotian","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Immunology State Key Laboratory of Complex, Severe, and Rare Diseases Institute of Basic Medical Sciences Chinese Academy of Medical 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