Lei Sun

Metabolic disorders encompass a spectrum of pathologies driven by the dysregulation of systemic metabolic homeostasis. Their escalating global prevalence has positioned these conditions at the forefront of contemporary biomedical research. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates cellular tyrosine phosphorylation and links metabolic perturbations to altered signal transduction. Functionally, PTPN2 modulates immune responses, cellular proliferation, and metabolic signaling pathways. Consequently, it influences immunological tolerance, glucose and lipid metabolism, and insulin sensitivity in a context-dependent manner. To facilitate the identification of novel therapeutic targets, this review systematically delineates the molecular mechanisms underlying PTPN2 function across diverse metabolic pathologies. Specifically, we examine its involvement in type 1 diabetes, type 2 diabetes, diabetic complications, and metabolic dysfunction-associated steatohepatitis. Furthermore, we highlight recent advances in PTPN2-targeted interventions, with a particular emphasis on type 2 diabetes research, while critically evaluating existing clinical challenges and future translational prospects. Ultimately, this synthesis provides an integrated perspective for the development of precision medicine strategies in the management of metabolic diseases.

Aim: The p38 MAPK pathway governs the core innate immune response in Caenorhabditis elegans ( C. elegans ), yet the negative regulatory networks preventing immune overactivation—and their potential as therapeutic targets—remain elusive. We aimed to identify novel phosphatase checkpoints in host defense, elucidate their molecular mechanisms, and validate their druggability using small-molecule interventions. Methods: We performed a genome-wide RNAi screen of 166 phosphatase genes in C. elegans infected with Pseudomonas aeruginosa (PA14) to identify key regulators. The molecular mechanism was dissected using yeast two-hybrid screening, Co-IP, and mutagenesis assays. Furthermore, a small-molecule screen was performed to identify compounds capable of interfering with PTP-4 function, followed by Surface Plasmon Resonance (SPR), molecular docking, and structural biology approaches to characterize compound–PTP-4 interactions. Results: PTP-4 was identified as a critical negative regulator of immunity. Genetic deficiency of ptp-4 significantly enhanced host resistance via hyperactivation of the p38 MAPK (PMK-1) pathway. Mechanistically, PTP-4 physically interacts with ATLN-1, an ER-shaping GTPase, through its phosphatase domain, thereby suppressing immune activation. Crucially, baicalin was identified through compound screening as an inhibitor of P. aeruginosa infection. Structural and biochemical analyses revealed a dual mechanism of action: baicalin directly binds to the PTP-4/ATLN-1 interface with high affinity (K _D = 28.69 μM) to allosterically disrupt their complex formation, while concurrently downregulating PTP-4 protein expression. This “dual-hit” inhibition mimics the genetic loss of ptp-4 , effectively unleashing the innate immune response. Conclusion: Our study uncovers the PTP-4/ATLN-1 axis in the control of P. aeruginosa infection. Importantly, we provide the first proof-of-concept that this axis is a druggable target. By demonstrating that baicalin boosts host immunity through the specific dismantling of the PTP-4/ATLN-1 complex, we highlight a novel therapeutic strategy for combating bacterial infections.

Berberine (BBR), an isoquinoline alkaloid extracted from Coptis chinensis , is clinically used to treat chronic colitis, diabetes, and other diseases. Although BBR has antitumor effects, it is unclear whether it can inhibit hepatocellular carcinoma (HCC) by modulating the tumor inflammatory microenvironment. In this study, we demonstrated that BBR inhibits HCC development in mice by suppressing the M2 polarization of macrophages. Using an H22 tumor-bearing xenograft mouse model, we found that BBR significantly inhibited H22 tumor growth. Analysis of scRNA-seq results revealed reduced M2 macrophage infiltration and polarization in BBR-treated HCC tissues. Pharmacodynamic studies showed that BBR treatment markedly increased CD8 ⁺ T cell infiltration and attenuated M2 polarization. In vitro , BBR suppressed IL-4 or tumor cell supernatant-induced M2 polarization, as evidenced by decreased expression of M2 polarization marker genes (Arg 1 , Retnla , etc.) and reduced JAK1/STAT6 phosphorylation levels. Molecular docking and protein stability assays revealed that BBR directly binds to JAK1’s FERM domain, stabilizing it. Combination therapy with BBR and anti-PD-L1 antibody synergistically inhibited H22 tumor growth. These findings suggest that BBR can reduce the M2 polarization of tumor-associated macrophages (TAMs) by targeting the IL-4-JAK1-STAT6 axis, and combining with anti-PD-L1 antibody may represent a promising therapeutic strategy to enhance BBR’s antitumor efficacy.

Tumor‐associated macrophages (TAMs) are one of the most abundant immune cells in solid tumors and play a critical role in tumor progression. This study found that the expression of LIM domain‐only protein 7 (LMO7) in TAMs is associated with poor patient survival. LMO7 deficiency significantly inhibited tumor growth and increased the accumulation of antitumor TAMs and CD8 ⁺ T cells. Specifically, single‐cell RNA sequencing (scRNA‐seq) reveals that LMO7‐deficient TAMs undergo an antitumor reprogramming, characterized by upregulated expression of pro‐inflammatory and phagocytosis‐related genes. Notably, LMO7 deficiency enhances immune‐mediated tumor confinement by regulating the phagocytic activity of TAMs. Mechanistically, LMO7 inhibits TAM phagocytosis by promoting the lysine 48‐linked polyubiquitination at lysine 45 of the β chain of the phagocytic receptor low‐density lipoprotein receptor‐related protein 1 (LRP1), leading to degradation via the ubiquitin‐proteasome system. Furthermore, combined targeting of LMO7 deficiency and SIRPα blockade demonstrates synergistic antitumor efficacy. Collectively, these findings demonstrate the critical role of LMO7 in orchestrating TAM phagocytosis and suggest that LMO7 inhibition is a promising drug target to enhance cancer immunotherapy.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease; however, effective clinical treatments for IPF are lacking. High serum amyloid A (SAA) expression in serum is closely related to the severity of pulmonary fibrosis, but the underlying mechanisms remain incompletely understood. This study found that the expression of endogenous SAA3 was significantly induced in mice with bleomycin-induced fibrosis. Saa3 deletion alleviated pulmonary fibrosis in mice. Additionally, recombinant IL-36α treatment aggravated fibrosis in bleomycin-induced Saa3^−/− mice. Furthermore, SAA3 could induce the expression of IL-36α in macrophages through the NF-κB pathway and transcription factor Krűppel-like factor 6 (KLF6). Also, the Klf6 knockdown alleviated severe lung fibrosis after recombinant SAA3 treatment. In conclusion, our study suggested that SAA3 aggravated bleomycin-induced pulmonary fibrosis by inducing IL-36α expression in macrophages through the NF-κB–KLF6 pathway. It provides new theoretical bases and potential therapeutic targets for treating fibrosis-related diseases.

Idiopathic pulmonary fibrosis (IPF) is a progressive lethal disease. Profibrotic fibroblast polarization during wound healing is one of the main causes of IPF, and the molecular mechanisms involved have yet to be fully determined. LIM domain-only protein 7 (LMO7), which acts as an E3 ubiquitin ligase, is highly expressed in the lung, brain and heart and plays important roles in embryonic development, cancer progression, inflammatory bowel disease and Dreifuss muscular dystrophy (EDMD). In this study, we investigated the role of LMO7 in pulmonary fibrosis. Bleomycin (BLM)-induced lung fibrosis was established in mice. For AAV-mediated gene therapy, AAV-Lmo7 shRNA (AAV-Lmo7 shRNA) was intratracheally administered 6 days before BLM injection. Through transcriptome analysis, we found that the expression of LMO7 was significantly upregulated in the fibroblasts of IPF patients and BLM-induced mice. Knockdown of LMO7 impaired the profibrotic phenotype of fibroblasts in BLM-treated mice and in primary lung fibroblasts stimulated with TGF-β in vitro. We observed that LMO7 binds to SMAD7, mediating its degradation by polyubiquitination of lysine 70 and increasing the stability of TGF-β receptor 1 (TGFβR1). Finally, intratracheal administration of adeno-associated virus (AAV)-mediated Lmo7 shRNA significantly ameliorated the progression of BLM-induced lung fibrosis. Our results suggest that LMO7 is a promising target for blocking profibrotic fibroblast polarization for the treatment of fibrotic lung disease. A model for the role of LMO7 in TGF-β/SMAD signaling during pulmonary fibrosis. During pulmonary fibrosis, ubiquitin E3 ligase LMO7 is up-regulated, and binds with. SMAD7. LMO7 mediates the ubiquitination of SMAD7 on Lysine 70, leading to its degradation, and further enhances the stability of transforming growth factor-beta receptor 1 (TGFβR1).

Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 10⁸ TCID₅₀) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8⁺ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

Asthma exacerbations caused by respiratory viral infections are a serious global health problem. Impaired antiviral immunity is thought to contribute to the pathogenesis, but the underlying mechanisms remain understudied. Here using mouse models we find that Cullin5 (CUL5), a key component of Cullin-RING E3 ubiquitin ligase 5, is upregulated and associated with increased neutrophil count and influenza-induced exacerbations of house dust mite-induced asthma. By contrast, CUL5 deficiency mitigates neutrophilic lung inflammation and asthma exacerbations by augmenting IFN-β production. Mechanistically, following thymic stromal lymphopoietin stimulation, CUL5 interacts with O-GlcNAc transferase (OGT) and induces Lys48-linked polyubiquitination of OGT, blocking the effect of OGT on mitochondrial antiviral-signaling protein O-GlcNAcylation and RIG-I signaling activation. Our results thus suggest that, in mouse models, pre-existing allergic injury induces CUL5 expression, impairing antiviral immunity and promoting neutrophilic inflammation for asthma exacerbations. Targeting of the CUL5/IFN-β signaling axis may thereby serve as a possible therapy for treating asthma exacerbations.