Acta Pharmacologica Sinica最新文献

Myocardial remodeling, an essential pathological development in cardiovascular disease, is largely determined by disruptions in redox homeostasis and mitochondrial bioenergetic function. Iristectorigenin A (ITG), a naturally occurring isoflavone, exhibits a variety of pharmacological effects, including antioxidant and anti-inflammatory activities. While so many protective effects, its specific effect on cardiac remodeling has not been reported previously. In this study, we aims to investigate the role of ITG in pressure overload-induced cardiac remodeling with a particular focus on mitochondrial function and oxidative stress. We revealed that ITG mitigated TAC-induced cardiac remodeling and improved cardiac function, with the 20 mg/kg dose showing optimal efficacy; further escalation to 40 mg/kg provided no additional benefit. ITG attenuated cardiomyocyte hypertrophy and inhibited activation of fibroblasts in vitro. Additionally, ITG treatment effectively suppressed oxidative stress and inflammation in the hearts of TAC mice, while improving mitochondrial morphology and the integrity of inner membrane structure. Notably, surface plasmon resonance (SPR) analysis indicated a direct interaction between SIRT6 and ITG with micromolar affinity. Besides, sustained TAC- or PE-stimulation impaired cardiac sirtuin 6 (SIRT6) protein levels, which were partially reversed by ITG. More importantly, silencing SIRT6 and SIRT6 knockdown separately inhibited the protective effects of ITG in vitro and in vivo. Mechanistically, ITG promotes SIRT6 levels by inhibiting its ubiquitination degradation. Furthermore, the cardioprotective effect of ITG was concomitant with SIRT6 upregulation, deacetylation and dephosphorylation of forkhead box protein O1 (FOXO1) and the subsequent increased transcription of antioxidant genes. Collectively, we firstly discover that ITG inhibits oxidative stress and safeguards mitochondrial morphofunctional homeostasis in response to pathological stress through activating SIRT6/FOXO1 axis, suggesting the therapeutic potential of ITG in the treatment of cardiac hypertrophy and remodeling, providing a promising avenue for future research and potential clinical application. Schematic illustration of ITG's potential protective mechanism against cardiac hypertrophy.

Chronic pain has emerged as the third leading health issue, following cardiovascular and cerebrovascular diseases and cancer. Clinically, patients with chronic pain often exhibit comorbid depression-like behaviors. However, the underlying mechanisms of chronic pain-related depression remain unclear. In this study, a chronic pain-related depression model was established in C57BL/6J, Vgat-Cre, and TH-Cre mice through sciatic nerve ligation (SNI) surgery. Viral-mediated DNA methyltransferase 1 (DNMT1) knockdown, optogenetic/chemogenetic modulation, electrophysiological recordings and molecular biology techniques were used to investigate the role of DNMT1 in regulating the projection from central amygdala GABAergic neurons (CeA^GABA) to locus coeruleus noradrenergic neurons (LC^NA) and its impact on chronic pain-related depression-like behaviors. Viral tracing identified LC as a major downstream target of the CeA. Immunohistochemical staining and electrophysiological recordings confirmed the functional synaptic connection between CeA-GABAergic neurons and LC-NAergic neurons. Behavioral assays showed the bidirectional modulation of pain-related depression phenotypes through LC-NAergic system: activation of LC-NAergic neurons induced depression-like behaviors, whereas their inhibition improved SNI-induced depression-like behaviors. Notably, CeA-GABAergic neurons were found to specifically innervate LC-NAergic neurons in mediating chronic pain-related depression-like behaviors. Furthermore, inhibition of the CeA^GABA → LC^NA circuit abolished the improvement of depressive behaviors in DNMT1 knockdown SNI mice, establishing DNMT1 as a key epigenetic regulator of this pathway. Taken together, our findings suggest that DNMT1 may suppress the GABAergic projections from the CeA to LC-NAergic neurons, thereby contributing to chronic pain-related depression-like behaviors. These findings provide novel insight into the circuit-related epigenetic basis of pain-depression comorbidity.

Colorectal cancer (CRC) ranks as the third most common malignancy worldwide, with metastasis representing the primary cause of mortality. Aberrant activation of the Wnt/β-catenin pathway drives epithelial‒mesenchymal transition (EMT) and CRC metastasis, making β-catenin a key therapeutic target. Josephin domain containing 2 (JOSD2), a deubiquitinase with protumorigenic roles in multiple cancers, has an undefined function in CRC metastasis. Herein, by screening a protein homeostasis-related inhibitor library, we identified HY041004, a reported JOSD2 inhibitor, which potently suppresses β-catenin transcriptional activity. Mechanistically, JOSD2 modulates β-catenin protein abundance and functional activity via the RAS-ERK signaling cascade rather than through direct deubiquitination of β-catenin. Functional assays further demonstrated that JOSD2 inhibition via RNA interference or pharmacological inhibition significantly attenuated CRC metastasis both in vitro and in vivo. Collectively, our findings identify JOSD2 as a critical oncogenic factor that promotes β-catenin activity and validate JOSD2 as an underlying therapeutic target for metastatic CRC (mCRC).

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with limited therapeutic options and a high incidence in East Asia. Gain-of-function mutations in nuclear factor erythroid 2-related factor 2 (Nrf2) are a major driver of ESCC progression, however, pharmacological interventions capable of effectively suppressing mutant Nrf2 signaling are currently lacking. Here, we conducted a high-throughput screen of 2141 natural products using Nrf2 reporter assays, fluorescence polarization, and Nrf2-dependent assays, and identified gambogenic acid (GNA) as a Nrf2-targeted inhibitor that preferentially attenuates oncogenic signaling driven by Nrf2 gain-of-function mutations in ESCC. GNA exhibited preferential anti-tumor activity in Nrf2-mutant ESCC cells compared with wild-type controls, both in vitro and in vivo. GNA also enhanced the chemosensitivity of Nrf2-mutant ESCC to cisplatin. Mechanistically, GNA suppressed the expression of Nrf2-driven ARE genes and modulated amino acid metabolism and mRNA translation by promoting cysteine oxidation in translational regulatory proteins within Nrf2-mutant cells. Importantly, GNA induced polymerization of the Nrf2/MafG protein complex and promoted its ubiquitin-mediated proteasomal degradation, thereby uncovering a previously uncharacterized mechanism of inhibition targeting the Nrf2/MafG axis. Collectively, our study identifies GNA as a promising therapeutic candidate that preferentially suppresses mutant Nrf2 signaling and shows therapeutic potential in Nrf2-driven ESCC.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid-beta (Aβ) aggregates, in the form of fibrils and plaques. While it has largely been stated that Aβ oligomers are the main toxic species, significant evidence indicates that fibrils may also be relevant to AD pathogenesis. Notably, evidence indicates that while fibrils, through direct interaction with neuronal membranes, contribute to synaptic dysfunction and cellular damage, no direct evidence between fibrils and their impact on neuronal functions, including plasticity, was investigated. This study inquired into the impact of Aβ fibrils complex on neuronal function and membrane integrity, shedding light on their contribution to synaptic defects. Aβ fibrils were generated from Aβ_1-42 oligomers, and their effects were evaluated on synaptic plasticity in ex vivo hippocampal slices from both female and male mice. Compared to Aβ_1-42 oligomers, fibrils induced more severe damage in synaptic plasticity, emphasizing their potent neurotoxicity effect underlying cognitive decline. Additionally, using a liposomal model to examine fibril-membrane interactions, it was observed that Aβ fibrils are able to affect membrane fluidity compared to the Aβ_1-42 oligomeric species, indicating that the size and aggregation state of Aβ fibrils are crucial for their toxicity. These findings challenge the view that oligomers are the primary toxic species in AD, showing that Aβ fibrils also play an active role in cellular dysfunction, promoting a synaptic dysfunction correlated to the cognitive impairment observed in AD.

Ischemic stroke is a leading cause of global mortality and long-term disability, with limited therapeutic options. Increasing evidence from experimental studies suggests that fibroblast growth factors (FGFs) play important roles in regulating key biological processes involved in brain repair following ischemia. This review examines the existing evidence to understand the functional roles of FGFs in ischemic stroke, highlighting findings from in vivo and in vitro models, as well as outcomes from clinical investigations. FGFs contribute to neuroprotection by supporting neuronal survival, modulating inflammatory responses, preserving blood-brain barrier (BBB) integrity, and enhancing angiogenesis. Despite promising data from experimental models, clinical translation of FGF-based therapies has proven challenging. Clinical trials have encountered issues such as safety concerns, particularly regarding optimal dosing and the risk of adverse effects, which complicates treatment response. These limitations highlight the complexity of translating FGF-based therapies into clinical practice in stroke treatment. Additionally, emerging FGF biomarkers may help predict therapeutic responses and guide patient selection and diagnosis. Future research should focus on optimizing delivery systems, identifying therapeutic windows, and improving clinical trial design, as successful clinical translation of FGF therapies relies on resolving subtype-specificity and refining delivery strategies to ensure targeted and effective treatment. Therefore, gaining a deeper understanding of the timing and context of FGF activity following ischemic stroke could pave the way for successful clinical applications, such as early neuroprotection, preservation of BBB integrity, and reduction of neuroinflammation. This understanding could also support the development of more targeted and effective interventions for ischemic stroke.

Colorectal cancer (CRC) remains a significant global health challenge, characterized by high post-surgical recurrence and poor survival outcomes. This study explores the therapeutic potential of odoroside A (OA), a natural compound derived from Nerium oleander, focusing on its ability to modulate lipid metabolism and induce cancer cell death on CRC. In a subcutaneous xenograft tumor model with HT29 and RKO cells, OA achieved inhibition ratios of 81.07% and 78.26% at a dose of 1.5 mg/kg, respectively. Mechanistic insights revealed that OA induced lipid accumulation and triggered cell death through lipid peroxidation, primarily by inhibiting fatty acid oxidation (FAO) pathways. This effect was supported by decreased mitochondrial FAO activity and reduced expression of FAO-related proteins, including CPT1A, CPT1B, CPT1C, CPT2, and ACSL1. Additionally, OA targeted ubiquitin-specific peptidase 8 (USP8), promoting the ubiquitination and degradation of liver X receptor beta (LXRβ), a critical regulator of lipid metabolism. This downregulation of LXRβ further disrupted FAO. This study establishes a foundation for developing OA as a natural compound-based anticancer therapy for CRC and identifies a novel link between USP8 and LXRβ, offering new insights into lipid metabolism on CRC.

N⁶-methyladenosine (m⁶A) is the most abundant internal modification of eukaryotic mRNA, and its dysregulation is increasingly linked to autoimmune diseases. Unlike previous reviews that broadly cover the entire m⁶A network, this review adopts an m⁶A writer centric perspective. The m⁶A writer complex serves as the upstream gatekeeper of epitranscriptomic regulation. We summarize its structural organization and cell‑type‑specific functions in controlling immune cell differentiation and function, as well as its protective roles in parenchymal tissues. Accumulating evidence shows that the writer complex exerts context‑dependent dual actions across a wide range of autoimmune conditions, including rheumatoid arthritis, lupus, psoriasis, and others. We also discuss the mechanistic basis of this functional heterogeneity, involving microenvironmental signals, subunit composition, and reader proteins. Notably, our review not only focuses on the roles and mechanisms of writer‑mediated m⁶A modification in various immune cells but also summarizes its pharmacological modulators, which represents a key advantage over previous reviews. By focusing specifically on the writer complex, we provide a more proximal and mechanistically feasible framework for precise epitranscriptomic intervention in autoimmune disorders.

Proteolysis-targeting chimeras (PROTACs) have redefined the paradigm of targeted protein degradation by hijacking the endogenous ubiquitin-proteasome system. However, their clinical translation remains hampered by "beyond-rule-of-five" (bRo5) physicochemical liabilities, including high polarity, limited membrane permeability, and unpredictable pharmacokinetic behavior, which collectively lead to suboptimal bioavailability and risks of non-specific systemic distribution. This review focuses on the chemistry-driven evolution of delivery strategies to transform these molecular liabilities into pharmacological advantages. By integrating medicinal chemistry with delivery science, we propose a conceptual framework to optimize target selectivity, enhance cellular uptake, and broaden the therapeutic window, providing systematic guidance for overcoming the bottlenecks of PROTAC in vivo applications. In terms of molecular design, innovations in prodrug and linker engineering, including photo-responsive, enzyme-activated, folate-targeted, and reactive oxygen species (ROS)-triggered systems, achieve precise spatiotemporal regulation and controlled release of PROTAC activity. The field of delivery vehicles encompasses lipid-based, polymeric, and inorganic nanoscaffolds, as well as antibody-PROTAC conjugates (DACs) and aptamer-PROTAC hybrids (APCs), providing multidimensional platforms for crossing biological barriers and achieving antigen-dependent targeting. Furthermore, the emergence of modular self-assembly, membrane-targeting strategies, and "split-and-hybrid" paradigms signifies a shift toward programmable medicinal chemistry that integrates physicochemical tuning with pharmacokinetic optimization. Future integration of chemically reconfigurable carriers with unified PK-PD evaluation systems will further accelerate the clinical translation of next-generation intelligent PROTAC therapeutics. Challenges and innovative strategies in PROTAC delivery system design. PROTAC is regarded as a novel therapeutic strategy with unlimited potential. However, the poor water solubility and low cell permeability of PROTAC result in poor pharmacokinetic properties, thereby limiting the clinical application of PROTAC. The development of PROTAC delivery systems can accelerate the pace of their transformation from experimental to clinical use. These delivery systems can optimize the physicochemical properties of PROTAC, achieve targeted delivery, promote intracellular accumulation and enhance its degradation efficacy.

Vascular diseases include disorders affecting arteries, veins, and capillaries, and remain the main cause of morbidity and mortality worldwide. The search for new therapeutic targets has led to the discovery of adenosine receptors as key regulators of the pathogenesis of several vascular conditions, including hypertension, atherosclerosis, abdominal aortic aneurysm, cerebral ischemia, and pathological angiogenesis. This review summarises the context-dependent functions of adenosine receptors in these diseases, with particular emphasis on mechanisms associated with endothelial-mesenchymal transition, vascular inflammation, and metabolic reprogramming. The therapeutic relevance of individual adenosine receptor subtypes is also discussed, including current preclinical evidence regarding receptor agonists and antagonists, as well as the potential value of combination-based approaches. Finally, current challenges and future research directions are considered, particularly the development of tissue-specific therapeutic strategies and the application of emerging technologies to improve the clinical translation of mechanistic findings.