Acta Pharmacologica Sinica最新文献

Major depressive disorder (MDD) is generally associated with synaptic damage in specific brain regions. However, the molecular mechanisms underlying the pathogenesis of MDD remain largely unknown. In the present study, we demonstrate that chronic stress-an established inducer of depression-like behaviors in animal models-upregulates the expression of protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2) in the hippocampal dCA1 region, a key regulator of the actin cytoskeleton and endocytic processes. The overexpression of PACSIN2 in CA1 hippocampal pyramidal neurons may increase the susceptibility to stress stimulation in rats through physical interactions with dynamin and cooperative modulation of the expression of postsynaptic membrane GluA1 AMPA receptors. Selective knockdown of PACSIN2 in the dCA1 hippocampal region of depressed rats significantly enhanced synaptic transmission, ultimately ameliorating depression-like behaviors. These findings provide direct evidence that abnormal function of hippocampal neurons resulting from perturbations in neuroplasticity may be involved in the pathogenesis of MDD. Moreover, PACSIN2 may serve as one of the underlying molecular controls through which chronic stress induces synaptic loss and dysfunction and the resulting behavioral disorders.

Cell-based immunotherapies have emerged as a transformative modality in modern cancer treatment, complementing conventional approaches such as surgery, chemotherapy, radiotherapy, and molecularly targeted therapies. This review provides an integrated and up-to-date synthesis of the rapidly evolving landscape of cellular immunotherapy, encompassing chimeric antigen receptor (CAR) T cells, T cell receptor (TCR)-engineered T cells, tumor-infiltrating lymphocytes (TILs), dendritic cell (DC) vaccines, natural killer (NK) cell-based therapies, and macrophage-directed strategies. We delineate the mechanistic foundations underlying each modality, summarize clinical outcomes across both hematologic malignancies and solid tumors, and critically evaluate therapeutic performance in the context of treatment-associated toxicities, resistance mechanisms, and barriers to durable response. Furthermore, we highlight emerging next-generation strategies designed to mitigate antigen escape, overcome immunosuppressive tumor microenvironments, and address challenges related to manufacturing, scalability, and accessibility. Collectively, these advances establish cell-based immunotherapies as a central component of precision oncology, with expanding potential to deliver durable and broadly accessible clinical benefit across diverse cancer types.

Fibrotic diseases, driven by excessive extracellular matrix deposition, account for substantial global morbidity and mortality, yet effective therapies remain elusive. Emerging evidence highlights impaired protein homeostasis as a key contributor to fibrosis, prompting exploration of autophagy-mediated degradation pathways. Here, we investigate the role of chaperone-mediated autophagy (CMA), a selective lysosomal degradation mechanism, in fibrosis progression. We demonstrate that CMA activity is suppressed in fibrotic tissues from experimental mice and human patients, correlating with pathological SMAD2/4 accumulation. Mechanistically, CMA deficiency impedes SMAD2/4 degradation, amplifying TGF-β signaling and collagen overproduction. AAV-mediated LAMP2A overexpression to restore CMA activity alleviated bleomycin-induced pulmonary fibrosis and carbon tetrachloride-induced hepatic fibrosis in mice. Furthermore, we identify sunitinib, an FDA-approved tyrosine kinase inhibitor, as a novel CMA activator that enhances LAMP2A transcription via targeting the transcription factor JUND, reduces SMAD2/4 levels, and mitigates fibrosis in vivo. Our findings establish CMA dysfunction as a common pathological hallmark of fibrotic diseases and unveil therapeutic strategies targeting CMA to restore protein homeostasis. This study provides critical insights into fibrosis pathogenesis and positions pharmacological CMA activation as a promising treatment avenue. CMA is impaired across fibrotic tissues, driving disease progression. Sunitinib activates CMA by targeting JUND to promote SMAD2/4 degradation, suppressing TGFβ-SMADs-fibrosis signaling. CMA, chaperone-mediated autophagy; IPF, idiopathic pulmonary fibrosis; PF, pulmonary fibrosis; HF, hepatic fibrosis.

Oxidative stress and inflammation play pivotal roles in the secondary brain injury following intracerebral hemorrhage (ICH). Our previous study on cerebral ischemia showed that TIGAR interacted directly with ATF4, thereby suppressing ATF4-mediated endoplasmic stress. In this study, we investigated whether TIGAR conferred protection against ICH by mitigating oxidative stress and inflammation and the regulatory mechanisms. ICH mouse model was established by microinjection of collagenase VII into the right striatum. Neurological dysfunction score was assessed at 24 h and 72 h post-ICH, and mice were sacrificed and the brains were collected at 72 h post-ICH. We found a significant elevation in TIGAR protein expression in the striatum of ICH mice with increased distribution of TIGAR protein among neurons, microglia and astrocytes. Deletion of TIGAR exacerbated neurological deficits and increased hematoma volume. Conversely, overexpression of TIGAR effectively mitigated neurological deficits, reduced hematoma volume and improved neuronal damage in ICH mice. We demonstrated that TIGAR overexpression significantly attenuated lipid peroxide 4-HNE as well as malondialdehyde content (a lipid oxidation product), while suppressing ROS production. In addition, TIGAR overexpression inhibited NLRP3 inflammasome expression along with caspase-1 cleavage. Moreover, TIGAR overexpression downregulated mRNA levels of inflammatory cytokines IL-1β and IL-6 while impeding microglial transformation into pro-inflammatory M1 phenotype. Intriguingly, TIGAR overexpression exerted inhibitory effects on the expression and activity of ATF4 and NOX4/p22phox involved in intracellular oxidative stress and inflammation regulation. In ICH mice, administration of NOX inhibitor GLX351322 (5 mg·kg^-1·d^-1, i.p. for 2 days) significantly ameliorated the intracerebral hemorrhage injury exacerbated by TIGAR knockdown. Collectively, we demonstrate upregulation of TIGAR proteins with enhanced distribution among neurons and glial cells post-ICH. TIGAR may alleviate oxidative stress and inflammation by inhibiting the ATF4/NOX4/p22phox signaling pathway, thereby reducing ICH-associated neuronal damage. The role and mechanism of TIGAR in intracerebral hemorrhage injury. TIGAR suppresses the ATF4/NOX4/p22phox axis, thereby reducing the production of reactive oxygen species (ROS), which subsequently alleviates oxidative stress and inflammatory responses to mitigate hemorrhagic injury.

Myocardial infarction (MI) continues to be a leading cause of global mortality. Resibufogenin (RBG), a principal bioactive constituent derived from Venenum Bufonis, is well recognized for its potent cardiotonic properties. Nevertheless, the therapeutic potential of RBG in the context of MI remains to be fully elucidated. This study revealed that RBG exerted significant cardioprotective effects in a murine model of MI by preserving cardiac function, attenuating myocardial injury, and increasing vascular density. Proteomic analysis revealed that angiogenesis was the predominant biological process associated with RBG-responsive proteins. Integrated proteomic analysis and mechanistic validation demonstrated that RBG activated the ITGA5-VEGF signaling axis, a pathway essential for its therapeutic efficacy, in a macrophage-dependent manner. Notably, both pharmacological inhibition of ITGA5 and depletion of macrophages completely abrogated RBG-mediated cardioprotection in the MI model. Furthermore, RBG significantly increased endothelial cell proliferation, migration, and tube formation in a macrophage-endothelial cell coculture system. More importantly, RBG upregulated ITGA5 expression in macrophages through activation of the VAV3/CDC42 signaling pathway. Collectively, these findings demonstrate that RBG is a promising therapeutic agent for myocardial infarction and acts via the macrophage-specific VAV3/CDC42-mediated ITGA5/VEGF signaling pathway to promote reparative angiogenesis. This study elucidates the cardioprotective effects and underlying mechanisms of RBG and establishes a scientific basis for the discovery of novel therapeutic agents from natural products.

Dysfunction of the autonomic nervous system (ANS) is strongly linked to the pathophysiological mechanisms of depression. Unfortunately, the correlation between depressive-like behaviors and the activation or inhibition of the sympathetic/parasympathetic nervous system has not been systematically explored. This study demonstrated that the pharmacological activation of sympathetic α-/β-adrenergic receptors increased stress susceptibility, whereas their antagonists enhanced stress resistance, thus suggesting a close correlation between sympathetic activity and depressive-like behaviors. Furthermore, arecoline, an agonist of the peripheral parasympathetic muscarinic (M) receptors, has exhibited significant antidepressant effects in multiple murine depression models, and its antidepressant effects could be blocked by the M receptor antagonist known as atropine, thus indicating that parasympathetic excitability regulates depressive-like behaviors. Moreover, arecoline acted on peripheral M receptors to activate glutamatergic neurons in the anterior cingulate cortex (ACC^Glu) via the vagus nerve and nucleus tractus solitarius (NTS) in sequence. Chemogenetic manipulation confirmed that the antidepressant effect of arecoline is dependent on the activation of ACC^Glu neurons, and direct activation of these ACC^Glu neurons exerts an antidepressant effect. Notably, pharmacological activation of peripheral parasympathetic M receptors can regulate the activation of the nodose ganglion (NG)-NTS-ACC^Glu neural axis and modulate depressive-like behaviors. For the first time, this study indicates that peripheral M receptors are promising targets for antidepressants development and proposes a potential antidepressant strategy involving the pharmacological modulation of peripheral autonomic balance.

Oncolytic virus M1 is a promising anticancer agent; however, its therapeutic efficacy is often limited by insufficient intratumoral viral replication and host antiviral immunity. Sirolimus, an mTOR inhibitor widely used in transplantation immunosuppression, has demonstrated potential to modulate antiviral responses. This study investigates whether sirolimus potentiates the efficacy of M1 virotherapy and elucidates the underlying mechanisms. Sirolimus significantly enhanced the antitumor efficacy of M1 virus in murine prostate cancer and liver cancer models, leading to reduced tumor growth. This synergistic effect remained evident in CD8⁺ T cell-depleted mice, indicating that the therapeutic benefit is independent of adaptive cytotoxic immunity. Mechanistically, sirolimus markedly increased M1 viral replication in tumor tissues, accompanied by enhanced tumor cell-cycle arrest and apoptosis. Notably, sirolimus selectively amplified viral load within tumors but not in normal organs, demonstrating tumor-specific viral enrichment and safety. Further analyses revealed that this increase in intratumoral virus was driven by mTOR pathway inhibition rather than alterations in macrophage or NK cell populations. Transcriptomic profiling and molecular validation indicated that sirolimus-mediated mTOR suppression downregulated key type I interferon-stimulated genes (Ifitm1, Stat1, Ifit3), thereby attenuating intrinsic antiviral defenses and facilitating viral amplification. In summary, sirolimus potentiates M1 oncolytic virotherapy by selectively enhancing viral replication in tumors via mTOR inhibition and suppression of type I interferon signaling, independent of CD8⁺ T cell-mediated immunity. These findings establish a mechanistic rationale for combining mTOR inhibitors with oncolytic viruses to achieve dual benefits of enhanced viral oncolysis and controlled immunosuppression, with translational relevance for cancer patients requiring long-term immunosuppressive therapy.

Epilepsy, a neurological condition, is characterized by frequent, spontaneous seizures. Both apolipoprotein E (ApoE) and TAM (Tyro3, Axl and MerTK) receptors, the key efferocytosis receptors, have been associated with the pathological mechanisms underlying epilepsy. Nevertheless, little is known about how they interact or the molecular mechanisms. Here, we explored how ApoE and microglial efferocytosis interact in a mouse model of acute seizures caused by kainic acid (KA). KA exposure reduced microglial efferocytosis that is dependent on growth arrest-specific protein 6 (Gas6)/MER proto-oncogene tyrosine kinase (MerTK). Additionally, KA treatment increased microglial ApoE expression, whereas ApoE knockout restored Gas6/MerTK-mediated microglial efferocytosis and alleviated KA-induced seizures and neuronal injury. Furthermore, KA exposure promoted ApoE immunoprecipitation with nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3). ApoE knockout suppressed KA-induced NLRP3 inflammasome activation. Interestingly, KA-induced seizures and neuronal injury were lessened by hippocampal NLRP3 knockdown, which further preserved Gas6/MerTK-dependent microglial efferocytosis. Furthermore, exogenous delivery of recombinant Gas6 had anti-seizure and neuroprotective benefits in addition to restoring microglial efferocytosis function. Collectively, ApoE stimulates NLRP3 inflammasome activation and targets Gas6/MerTK in seizure-prone mice, thereby impairing microglial efferocytosis. For the treatment of seizures, the ApoE-NLRP3-Gas6/MerTK axis may represent a potential therapeutic target.

Palbociclib, ribociclib, and abemaciclib, which are FDA-approved CDK4/6 inhibitors, constitute the standard first-line treatment for advanced hormone receptor-positive (HR⁺) breast cancers. Although these drugs share nominal targets and demonstrate comparable first-line efficacy, significant divergences exist in their cross-line therapeutic responses upon first-line progression, indicating distinct mechanisms of action. To systematically elucidate their similarities and differences, we employed quantitative proteomics and phosphoproteomics to investigate and compare the molecular expression characteristics induced by these drugs. As a result, the three CDK4/6 inhibitors exhibited distinct anti-proliferative potencies in HR⁺ breast cancer cells. Dynamic proteomic and phosphoproteomic profiling demonstrated cell cycle arrest and mTORC1 pathway downregulation by all inhibitors, with abemaciclib exerting the most potent suppression. Subsequent kinase activity analysis indicated an upregulation of AKT1 kinase activity following CDK4/6 inhibitor stimulation. Furthermore, acridine orange staining and flow cytometry indicated that abemaciclib elevated lysosomal proteins and acidification while increasing reactive oxygen species (ROS). Collectively, this study deepens the understanding of shared and drug-specific molecular characteristics and mechanisms of CDK4/6 inhibitors at multi-omic levels. Moreover, it provides an experimental basis and potential directions for customizing combination therapies based on pathway vulnerabilities, as well as exploration of novel therapeutic modes and drugs.

Endothelial and macrophage inflammation and sterol transport play an important role in atherogenesis. Serum/glucocorticoid-regulated kinase 1 (SGK1) is a member of the serine/threonine kinase family sharing approximately 54% identity with Akt. It has been implicated in smooth muscle cell calcification and macrophage inflammation during atherosclerosis; however, the role of SGK1 in endothelial dysfunction and endothelial or macrophage lipid metabolism is less characterized. In this study, we intraperitoneally injected high-cholesterol diet-fed male ApoE-knockout mice with the SGK1 inhibitor EMD638683 (10 mg/kg) every other day for 2 weeks, followed by histopathological and transcriptome analysis of the atherosclerotic lesion. To study the SGK1-associated mechanism in vascular inflammation in vitro, SGK1 silencing was performed in primary human umbilical vein endothelial cells (HUVECs), followed by treatment with pro-inflammatory cytokines. In THP-1-differentiated macrophages, SGK1 silencing followed by treatment with lipopolysaccharides was used. We showed that ApoE-knockout mice treated with EMD638683 show reduced atherosclerotic plaque area and attenuated endothelial and macrophage inflammation. Further transcriptome analysis of thoracic aortae showed that SGK1 inhibition downregulated inflammation and lipid metabolism-associated genes. In vitro, interleukin-1β treatment induces SGK1 phosphorylation. SGK1 inhibitor or siRNA reduced endothelial inflammation induced by pro-inflammatory cytokine treatments in HUVECs through nuclear factor κ light chain enhancer of activated B cell (NF-κB) signaling. In THP-1-differentiated macrophages, SGK1 inhibition or knockdown by siRNA is associated with reduced levels of pro-inflammatory cytokines, NF-κB, and sterol regulatory element binding protein 1 (SREBP1) pathway activation, following lipopolysaccharide treatment. SREBP1 inhibition by fatostatin or siRNA reduced p65 phosphorylation. In conclusion, the inhibition of SGK1 has been shown to reduce atherosclerotic plaque area and attenuate endothelial and macrophage inflammation in ApoE-knockout mice via NF-κB and SREBP1 signaling. These results not only contribute to our understanding of the complex interplay between vascular inflammation and lipid metabolism but also hold promise for the development of novel therapeutic strategies for atherosclerosis.