Shuai Wang

Ovarian cancer is a leading cause of gynecological cancer-related mortality, with its immunosuppressive tumor microenvironment (TME) limiting the effectiveness of immune checkpoint inhibitor therapy. Alanyl-tRNA synthetase 1 (AARS1) expression in ovarian cancer has been linked to poor prognosis; however, its immunological role remains unclear. In this study, we generated an Aars1-knockdown ID8 syngeneic mouse model to evaluate the role of AARS1 in vivo. Immune infiltration was assessed using flow cytometry and immunohistochemistry. Multi-omics profiling, including single-cell RNA sequencing (scRNA-seq), Ribo-seq, and ATAC-seq, was used to dissect underlying mechanisms. A small-molecule library screen, molecular dynamics simulations, and functional assays were used to identify compounds targeting AARS1. AARS1 depletion suppressed tumor progression, remodeled the TME, decreased myeloid-derived suppressor cells and tumor-associated macrophages, and increased cytotoxic T-lymphocyte (CTL) infiltration. Mechanistically, AARS1 interacted with NAT10 to regulate ribosomal loading of Irf7 mRNA, thereby attenuating type I interferon (IFN-I) signaling. Screening identified deleobuvir as a potent AARS1-binding molecule that disrupted the AARS1–NAT10–mRNA complex, restored IFN-I signaling, and enhanced antitumor immunity. Targeting AARS1 in ovarian cancer promotes CTL infiltration and sensitizes tumors to antitumor immunity.

The restoration of liver mass after partial hepatectomy (PH) and split liver transplantation (SLT) relies on efficient liver regeneration, a process highly susceptible to metabolic dysregulation. Although remodeling of the tricarboxylic acid (TCA) cycle is commonly observed during liver injury and regeneration, the specific role of succinic acid remains unclear. Here, we integrated radiomics, transcriptomics, metabolomics, and functional assays to systematically evaluate the association between succinic acid and liver regeneration. Multi-omics analysis of 20 SLT patients demonstrated that elevated succinic acid levels were strongly associated with impaired regenerative outcomes, and weighted gene co-expression network analysis identified the TCA cycle as a key regeneration-associated metabolic module. In a 70% PH mouse model, succinic acid administration was associated with reduced survival and decreased hepatocyte proliferation, consistent with impaired liver regeneration. Mechanistically, succinic acid exhibited distinct effects in different cell types: in macrophages, it enhanced inflammatory activation and increased interleukin-6 (IL-6) secretion, whereas in hepatocytes it reduced IL-6-induced STAT3 phosphorylation and downstream regenerative signaling. Furthermore, molecular docking, molecular dynamics simulations, and surface plasmon resonance assays supported an interaction between succinic acid and the STAT3 SH2 domain, providing structural evidence consistent with modulation of STAT3 signaling. Collectively, these findings suggest that succinic acid may function as an immunometabolic regulator that contributes to impaired liver regeneration by altering macrophage-derived IL-6 signaling and hepatocyte STAT3 activation. These findings also support further investigation of the succinic acid–STAT3 axis as a potential therapeutic target for promoting liver regeneration following hepatic injury or resection.

Supplementary Fig S6. PGE2 released by tumor cells under immune attack promotes CX3CR1 upregulation on macrophages

Supplementary Figure S3. The effect of CX3CR1 neutralizing antibody on macrophages

Supplementary Fig S5. In vitro co-culture experiments of TAM and CD8+ T cells and the effect of CX3CR1 overexpression on BMDMs

Table S3 from Blocking CX3CR1+ Tumor-Associated Macrophages Enhances the Efficacy of Anti-PD1 Therapy in Hepatocellular Carcinoma

Supplementary Figure S1. Flow cytometry and FACS gating strategy

Supplementary Figure S2. H22 orthotopic HCC immunotherapy model