Acta biochimica et biophysica Sinica最新文献

Retinal ischemia-reperfusion (I/R), a hallmark feature of many retinal degenerative diseases, often leads to irreversible neuronal damage. Among the various forms of cell death, necroptosis has emerged as a pivotal mechanism contributing to retinal neurodegeneration. Here, we identify a novel regulatory axis that modulates neuronal necroptosis using the long non-coding RNA (lncRNA) Pvt1. Using both in vitro (R28 cell line) and in vivo (intravitreal injection of adeno-associated virus carrying lncRNA Pvt1 shRNA in rats) models, the role of lncRNA Pvt1 under I/R in vivo and oxygen-glucose deprivation/reperfusion (OGD/R) in vitro is assessed. Comprehensive molecular and cellular analyses show that I/R or OGD/R induce robust necroptotic responses in neuronal cells. Notably, lncRNA Pvt1 knockdown significantly alleviates these necroptotic phenotypes by inhibiting RIPK3 phosphorylation. Mechanistically, lncRNA Pvt1 knockdown reduces Ppm1b promoter methylation, restoring PPM1B expression. Subsequently, PPM1B protein upregulation facilitates RIPK3 dephosphorylation, effectively dampening the necroptosis signaling cascade. These findings reveal that the previously unrecognized lncRNA Pvt1/PPM1B/p-RIPK3 axis is essential for neuronal survival following ischemic stress. This study provides compelling evidence that targeting the lncRNA Pvt1 is a promising therapeutic strategy for mitigating retinal neuronal necroptosis. Modulating this pathway provides new opportunities for the treatment of I/R-related retinal diseases.

Liver cancer, especially hepatocellular carcinoma (HCC), has become a global health-care challenge due to its high incidence and extremely poor prognosis. The tumor microenvironment (TME) plays a crucial role in cancer initiation, progression and therapy resistance. Although combination immunotherapies have revolutionized the clinical management of advanced HCC, therapeutic resistance still develops in many patients, which is partially attributed to the immunosuppressive effects of hepatic stellate cells (HSCs) and/or cancer-associated fibroblasts (CAFs) and the physical matrix barrier they create. As major components of the TME, HSCs are a major source of CAFs in liver cancer, and they both engage in fibrogenesis and cancer progression. However, non-specific CAF-targeting strategies demonstrate limited efficacy owing to the heterogeneity of CAFs in terms of transcriptional programs, phenotypes and functions. Advances in single-cell and spatial multi-omics techniques not only reveal the heterogeneity and functions of various subgroups of HSCs and CAFs, but also delineate the integrative spatiotemporal regulatory landscape of HSCs and CAFs in the TME. In this review, we summarize the specific biomarkers and diverse functions of distinct HSC and CAF subpopulations in liver cancer, highlighting the transitions between different states and their driving signals. We also focus on the spatial distribution and cellular interactions of HSCs and CAFs with their neighboring cells in liver cancer revealed by spatial transcriptomics and proteomics. Collectively, these insights into HSCs and CAFs provide potentially feasible strategies to alleviate resistance to immune checkpoint inhibitors and offer potential novel targets for liver cancer treatment.

Although homeotherms maintain a stable core body temperature through the coordinated regulation of multiple physiological systems, various factors can still lead to abnormal body temperature. While the immune-enhancing effects of fever are well understood, research on how low body temperature regulates immunity remains limited. Notably, cold therapy and hypothermia have been used to manage various diseases, including neurological and metabolic disorders. This review provides a comprehensive overview of the causes of hypothermia, its modulatory effects on immunity and underlying mechanisms, and its therapeutic applications in clinical diseases.

The establishment of the epidermal barrier is essential for terrestrial vertebrate survival. Retroviral-like aspartic protease 1 (ASPRV1), also known as skin aspartic protease (SASPase), plays a central role in this process by facilitating the initial cleavage of profilaggrin into filaggrin monomers, which is vital for skin hydration and barrier integrity. Mutations disrupting this activity are linked to hereditary skin disorders. Evolutionarily, ASPRV1 originated from the domestication of an ancient retroviral sequence and comprises a Gag-like domain and a C-terminal protease domain. While it shares structural similarity with HIV-1 protease (HIV-1 PR), the molecular basis for its unique enzymatic properties and substrate specificity remains unclear. Here, we present the biochemical characterization and crystal structures of mature human ASPRV1 (ASPRV1-14) in multiple states, including wild-type, catalytically inactive mutants bound to self-cleavage and filaggrin peptides, and a complex with the HIV-1 PR inhibitor indinavir. Our results demonstrate that ASPRV1-14 exhibits an ionic strength-dependent monomer-dimer equilibrium, shifting from a low-activity monomer at low ionic strength to a high-activity dimer at high ionic strength. Structural analysis reveals that ASPRV1-14 possesses distinctly hydrophobic S2/S2' pockets, dictating a strict requirement for hydrophobic residues at the P2/P2' positions of substrates and explaining its resistance to most HIV-1 PR inhibitors, except indinavir. Furthermore, analysis of disease-associated mutations indicates two main pathogenic mechanisms: disrupting the S2/S2' pocket ( e. g., V243A) or interfering with the self-cleavage maturation process ( e. g., I186T, K199E, R311C/P, and P314T). Collectively, these findings provide a comprehensive molecular framework for understanding the roles of ASPRV1 in epidermal homeostasis and the pathogenesis of skin diseases, offering insights for future therapeutic development.

7-Dehydrocholesterol (7-DHC) has recently emerged as an endogenous suppressor of lipid peroxidation/ferroptosis; however, its function in nutrient-poor microenvironments remains undefined. Here, we demonstrate that activated c-Myc directly occupies the DHCR7 promoter in pancreatic ductal adenocarcinoma (PDAC) cells, transcriptionally upregulating DHCR7, which converts 7-DHC into cholesterol, thereby fuelling PDAC cell proliferation. Under glucose deprivation, DHCR7 deletion triggers pronounced ferroptosis in PDAC cells, an effect that is sharply attenuated when glucose is supplemented. Mechanistically, DHCR7 inhibition drives 7-DHC accumulation, which plays a dual role: it traps free radicals (anti-ferroptosis) and yet simultaneously depletes the antioxidant pool (pro-ferroptosis), with the net outcome dictated by glucose availability. The antioxidant pool maintained by glucose is required to counteract the pro-peroxidation effects of 7-DHC; once glucose is limited, the radical-trapping-mediated anti-ferroptosis function of 7-DHC becomes negligible. Furthermore, glucose restriction in vitro and a low-glucose diet in vivo both sensitized PDAC cells to DHCR7 inhibition-triggered lipid peroxidation, which allows accelerated cell death or suppressed tumor growth. Collectively, 7-DHC, negatively regulated by the c-Myc/DHCR7 axis, promotes lipid peroxidation and ferroptosis in glucose-deficient PDAC tumors, revealing a metabolic vulnerability that can be exploited for therapy.

2-Ethylhexyl diphenyl phosphate (EHDPP), an aromatic organophosphate flame retardant (OPFR), is widely used in electronics, plastics, and textiles. While previous research has primarily focused on in vitro assays, the hepatotoxicity of EHDPP in mammals remains unclear. In the present study, six-week-old C57BL/6 mice are administered EHDPP via oral gavage for 28 days. First, EHDPP exposure leads to decreased body weights and significant hepatic accumulation of EHDPP (23.1 ng/g). Hepatic H&E staining, coupled with significantly elevated serum AST and ALT levels, demonstrates that the accumulation of EHDPP induces liver injury and inflammation. Targeted metabolomic analysis indicates reduced levels of free carnitine and acyl-carnitines in blood. RT-qPCR results confirm the marked suppression of key genes involved in hepatic lipid metabolism. Transmission electron microscopy (TEM) further reveals mitochondrial ultrastructural alterations following EHDPP exposure. Hepatic transcriptomic analysis identifies 79 and 579 differentially expressed genes (DEGs) in the EH-L and EH-H groups, respectively. Notably, Cyp2b10 displays a markedly high fold change in both the EH-L and EH-H groups. Furthermore, KEGG pathway enrichment and protein-protein interaction (PPI) analyses both exhibit that EHDPP exposure mainly affects lipid metabolism and drug metabolism. Within the PPI network modules, Cpt1a is identified as a critical hub protein. Molecular docking analysis predicts a potential interaction between EHDPP and the Cpt1A protein, and hepatic Cpt1A protein levels are significantly decreased after EHDPP exposure. Collectively, these findings provide novel insights into the mammalian health risks associated with EHDPP exposure.

The expression and secretion levels of antigenic proteins are critical determinants of mRNA vaccine efficacy. Signal peptides, which direct protein translocation into the endoplasmic reticulum (ER), have the potential to significantly enhance protein expression and immunogenicity, highlighting their value as engineering tools for mRNA vaccine design. This study adopts the SARS-CoV-2 RBD as a model antigen to screen a panel of signal peptides derived from common secretory proteins. The signal peptides from C3, IL-12, and IL-20 are identified as candidates capable of significantly promoting antigen expression and secretion. Fluorescence confocal microscopy reveals that these signal peptides enhance the targeting of mRNA to the ER at the subcellular level. In vivo experiments demonstrate that mRNA vaccines incorporating these engineered signal peptides induce stronger humoral and cellular immune responses. This study confirms that signal peptide replacement can enhance antigen expression, offering a potential strategy for improving the efficacy of mRNA vaccines.

Taraxasterol (TAR) exerts therapeutic effects on various liver diseases via its inherent hepatoprotective and anti-inflammatory properties. However, the mechanism by which TAR treats hepatic fibrosis remains unclear. This study aims to identify the potential targets and specific molecular mechanisms underlying the therapeutic effects of TAR on hepatic fibrosis. DDC- and CCl ₄-induced mouse models of hepatic fibrosis are established. The human hepatic stellate cell (HSC) line LX-2 and primary mouse HSCs are used for in vitro experiments. Transcriptomics, network pharmacology, single-cell transcriptomics, and molecular docking are employed to identify potential therapeutic targets of TAR for hepatic fibrosis. Functional validation is performed via HSD11B1 overexpression and knockdown experiments, and the regulatory role of the ERK MAPK pathway is verified using the specific inhibitor U0126. Histological staining results show that TAR significantly alleviates DDC- and CCl ₄-induced hepatic fibrosis in mice and reduces associated liver injury. In vitro assays reveal that TAR effectively reverses TGF-β-induced activation of LX-2 cells and primary mouse HSCs. Multi-omics and docking analyses identify HSD11B1 as a direct target of TAR, whose downregulation in activated HSCs is restored by TAR treatment. Functional experiments demonstrate that overexpression of HSD11B1 attenuates TGF-β-induced HSC activation, while HSD11B1 knockdown abolishes the therapeutic effects of TAR. Subsequent transcriptomic analysis confirms that HSD11B1 suppresses the ERK MAPK pathway, and knockdown of HSD11B1 compromises the therapeutic efficacy of the ERK MAPK inhibitor U0126. In summary, TAR alleviates liver fibrosis by inhibiting HSC activation through the HSD11B1-ERK MAPK axis.