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Here, by integrating population\u2010scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of &gt;500\u00a0000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1\n                    <jats:sup>G93A<\/jats:sup>\n                    mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology\u2010selective\u2013robust in SOD1\u2010driven models but shows no observable effect in TDP\u201043 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1\u2010OPTN signaling axis, restoring impaired autophagic flux through a PINK1\/Parkin\u2010independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet\u2010autophagy\u2010neuron axis that facilitates the co\u2010clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first\u2010in\u2010class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery\u2013opening a new frontier for ALS therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.76778","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:31:02Z","timestamp":1784806262000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Blood\u2010Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN\u2010Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1"],"prefix":"10.1002","volume":"13","author":[{"given":"Qingjian","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine First Affiliated Hospital of Wenzhou Medical University and Department of Neurology First Affiliated Hospital of Wenzhou Medical University  Wenzhou 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Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine First Affiliated Hospital of Wenzhou Medical University and Department of Neurology First Affiliated Hospital of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine First Affiliated Hospital of Wenzhou Medical University and Department of Neurology First Affiliated Hospital of Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqin","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Laboratory of Hebei Province The Second Hospital of Hebei 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