Paclitaxel　(PTX)　is　capable　of　aggravating　radiation-induced　pulmonary　fibrosis　(RIPF),　but　the　mechanism　is　unknown.　Spry2　is　a　negative　regulator　of　receptor　tyrosine　kinase-related　Ras/Raf/　extracellular　signal　regulated　kinase　(ERK)　pathway.　This　experiment　was　aimed　at　exploring　whether　the　aggravation　of　RIPF　by　PTX　is　related　to　Spry2.　The　RIPF　model　was　established　with　C57BL/6　mice　by　thoracic　irradiation,　and　PTX　was　administered　concurrently.　Western　blot　was　used　to　detect　the　expression　level　of　ERK　signaling　molecules　and　the　distribution　of　Spry2　in　the　plasma　membrane/cytoplasm.　Co-immunoprecipitation　(co-IP)　and　immunofluorescence　were　used　to　observe　the　colocalization　of　Spry2　with　the　plasma　membrane　and　tubulin.　The　results　showed　that　PTX-concurrent　radiotherapy　could　aggravate　fibrotic　lesions　in　RIPF,　downregulate　the　content　of　membrane　Spry2,　and　upregulate　the　levels　of　p-c-Raf　and　p-ERK　in　lung　tissue.　It　was　found　that　knockdown　of　Spry2　in　fibroblast　abolished　the　upregulation　of　p-c-Raf　and　p-ERK　by　PTX.　Both　co-IP　results　and　immunofluorescence　staining　showed　that　PTX　increased　the　binding　of　Spry2　to　tubulin,　and　microtubule　depolymerizing　agents　could　abolish　PTX＇s　inhibition　of　Spry2　membrane　distribution　and　inhibit　PTX＇s　upregulation　of　Raf/ERK　signaling.　Both　nintedanib　and　ERK　inhibitor　were　effective　in　relieving　PTX-exacerbated　RIPF.　Taken　together,　the　mechanism　of　PTX＇s　aggravating　RIPF　was　related　to　its　ability　to　enhance　Spry2＇s　binding　to　tubulin,　thus　attenuating　Spry2＇s　negative　regulation　on　Raf/ERK　pathway.　SIGNIFICANCE　STATEMENT　This　study　revealed　that　paclitaxel　(PTX)　concurrent　radiation　therapy　exacerbates　radiation-induced　pulmonary　fibrosis　during　the　treatment　of　thoracic　tumors,　which　is　associated　with　PTX　restraining　Spry2　and　upregulating　the　Raf/extracellular　signal　regulated　kinase　signaling　pathway,　and　provided　drug　targets　for　mitigating　this　complication.