The　process　of　erythroid　differentiation　is　orchestrated　at　the　molecular　level　by　a　complex　network　of　transcription　factors.　Erythroid　Krüppel-like　factor　(EKLF/KLF1)　is　a　master　erythroid　gene　regulator　that　directly　regulates　most　aspects　of　terminal　erythroid　differentiation.　However,　the　underlying　regulatory　mechanisms　of　EKLF　protein　stability　are　still　largely　unknown.　In　this　study,　we　identified　Vacuolar　protein　sorting　37　C　(VPS37C),　a　core　subunit　of　the　Endosomal　sorting　complex　required　for　transport-I　(ESCRT-I)　complex,　as　an　essential　regulator　of　EKLF　stability.　Our　study　showed　that　VPS37C　interacts　with　EKLF　and　prevents　K48-linked　polyubiquitination　of　EKLF　and　proteasome-mediated　EKLF　degradation,　thus　enhancing　EKLF　protein　stability　and　transcriptional　activity.　VPS37C　overexpression　in　murine　erythroleukemia　(MEL)　cells　promotes　hexamethylene　bisacetamide　(HMBA)-induced　erythroid　differentiation　manifested　by　up-regulating　erythroid-specific　EKLF　target　genes　and　increasing　benzidine-positive　cells.　In　contrast,　VPS37C　knockdown　inhibits　HMBA-induced　MEL　cell　erythroid　differentiation.　Particularly,　the　restoration　of　EKLF　expression　in　VPS37C-knockdown　MEL　cells　reverses　erythroid-specific　gene　expression　and　hemoglobin　production.　Collectively,　our　study　demonstrated　VPS37C　is　a　novel　regulator　of　EKLF　ubiquitination　and　degradation,　which　plays　a　positive　role　in　erythroid　differentiation　of　MEL　cells　by　enhancing　EKLF　protein　stability.　©　2023　Elsevier　Inc.