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Pharmacological or genetic reduction of BH4 levels has analgesic effects in rodent models of neuropathic and inflammatory pain, but also affects neurological and cardiovascular functions. Little is known about the downstream mechanisms of BH4 that could be targeted to attenuate BH4\u2010induced pain hypersensitivity without lowering BH4 levels. In this study, we exposed ex\u00a0vivo\u2010cultured rat dorsal root ganglion (DRG) neurons to BH4 and analyzed the activity of the sensory neuron\u2010sensitizing kinase ERK1\/2 via high\u2010content imaging. We show that BH4 exposure leads to increased pERK1\/2 levels in a dose\u2010 and time\u2010dependent manner. Interestingly, we found that H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    , as a by\u2010product of BH4 oxidation and not BH4 itself, induces increased pERK1\/2 levels via MEK1\/2 and B\u2010Raf (but not A\u2010Raf or C\u2010Raf) and that this can be blocked by pharmacological interference. In conclusion, elevated BH4 levels, as observed in various pain conditions, may drive sensory neuron sensitization via oxidation\u2010derived H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    and the B\u2010Raf\u2010MEK1\/2\u2010ERK1\/2 axis, which presents a novel pathway that could be targeted to attenuate BH4\u2010induced pain hypersensitivity without the necessity to reduce BH4 levels.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70271-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70271","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T09:45:27Z","timestamp":1762163127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>BH4<\/scp>\n                    Oxidation\u2010Derived\n                    <scp>\n                      H\n                      <sub>2<\/sub>\n                      O\n                      <sub>2<\/sub>\n                    <\/scp>\n                    Activates\n                    <scp>ERK1<\/scp>\n                    \/2 Signaling via B\u2010Raf in Rat Dorsal Root Ganglion Neurons"],"prefix":"10.1111","volume":"169","author":[{"given":"Milad","family":"Mohammadi","sequence":"first","affiliation":[{"name":"Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne University of Cologne  Cologne 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