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Background Liver regeneration requires intracellular NAD homeostasis to sustain rapid hepatocyte proliferation. Although nicotinamide (NAM) is a primary NAD precursor, its therapeutic efficacy in hepatic repair remains unknown. This study aims to investigate the specific impact of NAM supplementation on liver regeneration and elucidate the underlying molecular and immunological mechanisms.Methods We utilized 70% partial hepatectomy (PHx) and acetaminophen (APAP)-induced liver injury mouse models. The effects of exogenous NAM supplementation, pharmacological inhibition of NAM clearance (NNMT inhibition), and treatment with the non-inhibitory NAD precursor isonicotinamide (INAM) were evaluated. Mechanistic insights were obtained through single-cell RNA sequencing (scRNA-seq), flow cytometry, co-immunoprecipitation (Co-IP), and PMN-MDSC recruitment assays.Results NAM supplementation or blocking its clearance via NNMT inhibition significantly impaired liver regeneration and exacerbated injury, despite increasing total hepatic NAD levels ( IDDF2026-ABS-0304 Figure 1. NAM supplementation or NNMT inhibitors impair liver regeneration). Mechanistically, supraphysiological NAM functioned as a competitive feedback inhibitor of SIRT2, leading to the hyperacetylation and ubiquitin-proteasomal degradation of the transcription factor C/EBPβ (IDDF2026-ABS-0304 Figure 2. NAM supplementation decreases SIRT2 level and induces the hyperacetylation and ubiquitin-proteasomal degradation of C/EBPβ). Deficiency of C/EBPβ blunted the transcription of chemokines Cxcl1 and Cxcl2, thereby inhibiting the hepatic recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) (IDDF2026-ABS-0304 Figure 3. PMN-MDSCs are accumulated and drive liver regeneration, IDDF2026-ABS-0304 Figure 4. NAM regulates the migration of PMN-MDSC). These PMN-MDSCs were found to be essential for establishing a pro-regenerative immune niche via IL-1β secretion (IDDF2026-ABS-0304 Figure 5. PMN-MDSC-derived IL-1β promotes liver regeneration). To circumvent this axis, treatment with INAM—a structural isomer that supports NAD synthesis without inhibiting SIRT2—significantly accelerated liver repair and maintained robust PMN-MDSC infiltration (IDDF2026-ABS-0304 Figure 6. INAM promotes liver regeneration without inhibiting SIRT2).Conclusions Our study identifies a NAM-SIRT2-C/EBPβ signaling axis that limits the efficacy of traditional NAM-based NAD-boosting therapies in the liver. We propose that INAM serves as a promising metabolic modulator for optimizing liver repair by maintaining SIRT2 activity and the subsequent pro-regenerative immune response.Abstract IDDF2026-ABS-0304 Figure 1Abstract IDDF2026-ABS-0304 Figure 2Abstract IDDF2026-ABS-0304 Figure 3Abstract IDDF2026-ABS-0304 Figure 4Abstract IDDF2026-ABS-0304 Figure 5Abstract IDDF2026-ABS-0304 Figure 6