Acta Pharmacologica Sinica最新文献

The sigma-1 receptor is an important new therapeutic drug target for Alzheimer's disease (AD). Here, we reported that SOMCL-668, a novel selective and potent sigma-1 receptor allosteric modulator, is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted PC12 cells against Aβ-induced intracellular reactive oxygen species (ROS) accumulation, mitochondrial membrane potential hyperpolarization and neuronal apoptosis. Similar results were obtained in SH-SY5Y and primary cortical culture neurons. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB, while pharmacological inhibition or knockout of ERK via CRISPR-Cas9 attenuated its protective effects. Further studies with the sigma-1 receptor agonists/antagonists and knockout of sigma-1 receptor via CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 provides neuroprotection in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer's disease.

N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels that are ubiquitously expressed throughout the central nervous system (CNS) and serve as crucial mediators of neural development and synaptic plasticity. Dysregulation of NMDA receptor activity has been implicated in a wide spectrum of neurological and psychiatric disorders. In recent years, substantial progress has been made in the clinical development of small-molecule modulators targeting NMDA receptors. In this review, we summarize recent advances in this rapidly evolving field. Among various therapeutic indications, depression has emerged as an especially active area of investigation, with mechanistically diverse compounds ranging from broad-spectrum channel blockers (ketamine, dextromethorphan, esmethadone) to glycine site modulators (rapastinel, 4-chlorokynurenine, D-cycloserine) and allosteric modulators (apimostinel, zelquistinel), progressing through clinical pipelines. Beyond depression, NMDA receptor-targeted drug discovery is also advancing in other challenging CNS disorders, including neurodegenerative diseases (salzanemdor, NYX-458), pain (NYX-2925), epilepsy (radiprodil), and stroke (nelonemdaz, NP10679). Collectively, these developments reflect the maturation of NMDA receptor pharmacology and reaffirm the broad therapeutic potential of NMDA receptor modulation, while highlighting promising directions for future drug discovery.

Na_v1.5 is the main sodium channel subtype in the heart, playing a crucial role in maintaining regular cardiac electrical activity. It is a well-established therapeutic target for class I antiarrhythmic drugs used to treat both inherited and acquired arrhythmias. In this study, we report a highly effective (IC₅₀ = 1.38 ± 0.28 μM) and novel Na_v1.5 inhibitor, KH2, identified through an integrated drug discovery approach. Molecular dynamics (MD) simulations and experimental findings reveal that, unlike traditional class I antiarrhythmic drugs, KH2 shows a completely novel binding mechanism. Moreover, using electrophysiological mapping systems on rat isolated hearts, we found that KH2 significantly reduced cardiac conduction, highlighting its potential as a therapeutic agent for arrhythmias. Our finding of KH2 provided a valuable reference for designing drugs targeting Na_v1.5 to treat arrhythmias.

In the etiology of cancer, p62 is a well-known autophagic receptor and signaling adapter. High p62 expression is known to accelerate hepatocellular carcinoma (HCC) growth by activating various downstream signaling pathways. In this study, we investigated the activity of elevated p62 and its associated regulatory mechanisms during HCC progression. By conducting immunohistochemical staining on a human liver tissue microarray including 10 liver cancer tissues and 10 paracancerous tissues, we found that the expression levels of p62 and oncoprotein LAMTOR5 were markedly increased in HCC tissues compared with noncancerous tissues; LAMTOR5 was positively associated with p62 expression, and high LAMTOR5 or p62 expression predicted reduced overall and release-free survival. Transcriptomic analysis revealed that LAMTOR5 overexpression inhibited autophagy in HepG2 cells. We demonstrated that LAMTOR5 interacted with the LC3-interacting region domain of p62 and inhibited autophagy caused by the binding of p62 to LC3, thereby leading to the accumulation of p62 protein in HCC. Moreover, LAMTOR5 blocked p62 ubiquitination-mediated proteasome degradation, which increased the stability of p62. Functionally, p62 overexpression reversed LAMTOR5 deficiency-reduced hepatoma cell proliferation in vitro and in vivo. Lenvatinib, a multi-receptor tyrosine kinase inhibitor, significantly suppressed HCC growth in vitro and in vivo by downregulating LAMTOR5 and p62 expression. We conclude that LAMTOR5-mediated p62 stabilization is a novel HCC growth mechanism, targeting this axis as a promising therapeutic strategy.

The cGAS-STING cytosolic DNA-sensing pathway is a key mediator of the innate immune response and plays a crucial role in antitumor immunity. The expression of cGAS and STING is often suppressed in tumor cells, and reduced expression is associated with poor prognosis and inferior response to immunotherapy. In this study we systematically investigated the expression pattern of cGAS-STING pathway in tumors and its correlation with immunotherapy response. We showed that the expression of cGAS and STING was significantly decreased or undetectable in most breast cancer and murine tumor cell lines, while high cGAS and STING expression was associated with increased T cell infiltration, elevated PD-L1 and PD-1 levels, improved immunotherapy response and prolonged survival. In cGAS-STING-deficient MDA-MB-453 cells, DNMT inhibitor decitabine (DAC, 0.05-1 μM) dose-dependently restored the impaired pathway by reversing DNA methylation-mediated silencing. Furthermore, DAC combined with a chemotherapeutic agent cisplatin significantly enhanced the antitumor effect in MDA-MB-453 and MDA-MB-231 cells by activating the cGAS-STING pathway through cytoplasmic DNA accumulation. In addition, DNMT inhibition elevated intracellular dsRNA levels and activated the RIG-I/MDA5-MAVS pathway. These results suggest that DNMT inhibitors can epigenetically reprogram the cGAS-STING pathway, activate the RIG-I/MDA5-MAVS pathway, and in combination with chemotherapeutic agents, synergistically promote antitumor immunity. Together, this study identifies cGAS-STING as a potential predictor of immunotherapy response and highlights a novel therapeutic strategy for restoring innate immune function in cancer. Loss of cGAS-STING signaling in tumors impairs antitumor immunity and correlates with poor immunotherapy response. DNMT inhibition restores cGAS-STING pathway and concurrently activates the RIG-I/MDA5-MAVS signaling, synergistically enhancing immune infiltration and antitumor efficacy.

Acetaminophen (APAP)-induced liver injury (AILI) is a leading cause of acute liver failure, with limited preventive or therapeutic options. The role of betaine-homocysteine methyltransferase (BHMT), a key enzyme in the methionine cycle, remains unclear. We found that BHMT, primarily expressed in hepatocytes, showed reduced expression in the liver but elevated serum levels in the APAP-induced liver injury (AILI) mouse model. GalNAc-mediated targeted knockdown of Bhmt in hepatocytes aggravated AILI in mice. Through RNA-seq screening, we found that Bhmt deficiency dramatically suppressed stearoyl-coenzyme A desaturase 1 (SCD1) expression. Knockdown of Scd1 also exacerbated AILI. Mechanistically, Bhmt knockdown decreased the DNA methylation of BACH1 (BTB and CNC homology 1), a transcriptional factor, leading to upregulated BACH1 expression in primary mouse hepatocytes (PMHs) treated with APAP. BACH1 then bound to the enhancer region of Scd1, transcriptionally repressing SCD1. Lipidomic analysis revealed that Bhmt or Scd1 deficiency reduced levels of intracellular unsaturated fatty acids, particularly oleic acid (OA), whereas SCD1 overexpression increased OA levels and decreased lipid peroxides. OA administration alleviated AILI and mitigated the hepatotoxicity associated with Bhmt or Scd1 knockdown. Our findings indicate that BHMT mitigates AILI via the BACH1-SCD1-OA axis, suggesting that BHMT could serve as a preventive target for AILI, while increasing OA intake may offer dietary benefits for patients.

Mitochondrial DNA (mtDNA) damage and accumulation activate the cGAS-STING DNA-sensing pathway, which promotes immune clearance of tumor cells. Maintenance of the cytosolic level of mtDNA is key to sustain immune activation. T cell malignancies (T-CMs) are a general name of diseases with abnormal clonal proliferation of T lymphocytes at various stages. Immunotherapy of T-CMs is challenged by the lack of specific antigens to discriminate T-CMs from normal T cells. As intrinsic STING activation can promote the clearance of T-CMs by immune cells, we herein explored whether isoliensinine (IsoL), a natural compound from Nelumbinis Plumula could enhance NK clearance by mtDNA-mediated immune responses in tumor cells. To investigate whether IsoL modulated immune recognition and clearance of T-CMs, we pre-treated three T-CM cell lines (Jurkat, Molt4 and Hut102) with IsoL then co-cultured with NK-92MI cells. We showed that IsoL pre-treatment promoted cytosolic mtDNA accumulation by inducing ROS-dependent mitochondrial damage and inhibiting mitophagy via peroxiredoxin 1 (PRDX1), an antioxidant enzyme. Loss of PRDX1 in T-CMs also induced ROS-dependent mitochondrial DNA damage, and blocked mitophagy by preventing accumulation of mature PINK1, which was required to initiate mitophagy via recruiting Parkin to the damaged mitochondria. Remarkably, IsoL could induce expression of activating ligands in vitro, enhance NK cell infiltrations, and increase apoptosis of T-CMs. Moreover, we demonstrated that IsoL could sensitize T-CMs for NK clearance in vitro and in vivo. These results suggest that IsoL could be a potential therapeutic agent to enhance immune therapy of T-CMs.

N-methyl-D-aspartate receptors (NMDARs) are calcium-permeable ionotropic glutamate receptors broadly expressed throughout the central nervous system, where they play crucial roles in neuronal development and synaptic plasticity. Among the various subtypes, the GluN1/GluN3A receptor represents a unique glycine-gated NMDAR with notably low calcium permeability. Despite its distinctive properties, GluN1/GluN3A remains understudied, particularly with respect to pharmacological tools development. This scarcity poses challenges for deeper investigation into its physiological functions and therapeutic relevance. In this study, we employed a hybrid virtual screening (VS) pipeline that integrates ligand-based and structure-based approaches for the efficient and precise identification of small-molecule candidates targeting GluN1/GluN3A. A large compound library comprising 18 million molecules was screened using an AI-enhanced multi-stage method. The initial phase utilized shape similarity ranking via ROCS-BART, followed by refinement with a graph neural network (GNN)-based drug-target interaction model to enhance docking accuracy. Functional validation using calcium flux (FDSS/μCell) identified two compounds with IC₅₀ values below 10 μM. Of these, one candidate exhibited potent inhibitory activity with an IC₅₀ of 5.31 ± 1.65 μM, which was further confirmed through manual patch-clamp recordings. These findings highlight an AI-enhanced VS workflow that achieves both efficiency and precision, providing a promising framework for exploring elusive targets such as GluN1/GluN3A.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of nigral dopaminergic neurons and abnormal accumulation of α-synuclein. Our recent study has shown that α-synuclein induces cellular senescence prior to the loss of dopaminergic neurons and the onset of motor dysfunction. Microglia are known to contribute to dopaminergic neurodegeneration, primarily through NLRP3-mediated neuroinflammatory mechanism or by facilitating the propagation of α-synuclein. In this study, we identified the cell type susceptible to α-synuclein-induced cellular senescence in the substantia nigra and investigated the specific role of microglia with a particular focus on the NLRP3 inflammasome. PD mouse model was established by bilateral microinjection of viaAAV2/9 vectors encoding human α-syn-A53T into the SNpc to overexpress human mutant α-synuclein-A53T. We showed that overexpression of α-synuclein-A53T (α-syn-A53T) for 1 week not only induced a pro-inflammatory phenotype in nigral microglia but also led to the acquisition of a senescent state in a subset of microglial cells. Depletion of microglia by administration of the CSF1R inhibitor PLX5622 (1200 ppm) in diet for 1 week significantly attenuated α-synuclein aggregation, iron dysregulation and cellular senescence in the substantia nigra of PD mouse model. Transcriptomic and immunostaining analyses revealed that α-syn-A53T promoted senescence in nigral dopaminergic neurons via the SATB1/DNA damage/p21 signaling pathway, evidenced by reduced SATB1 expression along with increased levels of γ-H2A.X and p21 in TH-positive dopaminergic neurons within the substantia nigra. Moreover, genetic knockout of NLRP3 effectively mitigated α-syn-A53T-induced cellular senescence in these neurons by suppressing the SATB1/DNA damage/p21 signaling pathway. These results highlight the critical role of microglia in promoting dopaminergic neuronal senescence and suggest that NLRP3 may serve as a promising therapeutic target for early intervention in PD to mitigate neuronal senescence and subsequent neurodegeneration.