Acta Pharmacologica Sinica最新文献

G protein-coupled receptor kinase 2 (GRK2) is a key player in signal transduction and contains an N-terminus, a kinase domain (KD) and a C-terminus. Changes in the configuration of GRK2 regulate its allosteric effects, including KD closure and protein binding, and the interaction between the KD and the pleckstrin homology (PH) domain modulates the kinase activity of GRK2. GRK2 functions as a central molecule within a complex interactome, interacting with various cytoplasmic or membrane proteins in addition to G-protein coupled receptors (GPCRs), and plays a significant role in several GRK2 dysfunction-related diseases, including arthritis and cardiovascular disorders. Recently, GRK2 inhibitors-including peptide-based inhibitors, RNA aptamers, and small-molecule compounds-have been developed on the basis of targeted blockade of the GRK2-Gαq interface, GRK2-Gβγ interaction, and GRK2 KD-substrate binding, offering hope for the treatment of GRK2 dysfunction-related diseases. However, owing to the unfavourable properties of some small-molecule inhibitors and rapid degradation of peptides, the entry of these GRK2 inhibitors into clinical trials is limited. Understanding the regulation, activity, levels, or specific interactions of GRK2 is crucial for overcoming these challenges and optimizing the clinical use of GRK2 inhibitors. Our current review discusses the structure and function of GRK2, the research progress on GRK2 inhibitors and the regulatory role of GRK2 inhibitors in GRK2 dysfunction-related diseases to provide a significant theoretical basis for extensive research on GRK2-targeted therapies.

Cellular metabolism critically influences tumor resistance. Biophysical stimulations such as mechanical vibration and electrical pulses can reprogram mesenchymal stem cells (MSCs) and T cells into tumor-suppressive states. Here, we investigated whether optical pulses (OP) could similarly promote an anti-tumor microenvironment. Using mechanical and electrical stimulation as controls, we examined optically stimulated MSCs and T cells and their conditioned medium (CM) in breast cancer and osteoclast models. OP elicited color-specific effects: blue light induced direct tumor cell death, whereas green and red light converted MSCs into induced tumor-suppressing (iTS) cells. This conversion was mediated by OPN4, independent of the Piezo1 pathway engaged by mechanical and electrical cues. Green/red pulses enhanced nucleosome scattering, increased the NAD⁺/NADH ratio, reduced the repressive histone mark H3K9me3, and activated demethylases KDM3A/KDM4. Proteomic profiling revealed enrichment of transferrin receptor (TFRC) and Annexin A2 (ANXA2) in CM, which may suppress tumors via CD44 interaction and are associated with reduced immune-evasive signaling, including Programmed Death-Ligand 1 (PD-L1). These findings demonstrate that visible light pulses can epigenetically reprogram MSCs and T cells, offering a potential therapeutic strategy for breast cancer and bone metastasis.

Emerging evidence underscores the pivotal role of CD4⁺ effector T cells in antitumor immunity, yet their full therapeutic potential remains underexplored. This study investigates the impact of targeting the Wnt coactivators B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) on CD4⁺ T cell-mediated antitumor immunity. We demonstrate that either genetic deletion or pharmacological inhibition of BCL9/BCL9L suppresses tumor progression and increases CD4⁺ T cell activation in the tumor microenvironment (TME). Critically, loss of Bcl9/Bcl9l skews CD4⁺ T cell differentiation toward a Th1 phenotype at the expense of Th2, Th17, and Treg lineages, thereby establishing a Th1-dominant TME and unleashing a direct cytotoxic program in these Th1 cells. Mechanistically, BCL9/BCL9L inhibition promotes Th1 polarization by suppressing TCF4-mediated regulation of PIAS family genes and enhancing STAT1/STAT4 activation, thereby driving a potent Th1-mediated antitumor response. Collectively, our findings identify BCL9/BCL9L as critical negative regulators of CD4⁺ T cell antitumor immunity and establish them as promising therapeutic targets for reprogramming the TME toward a Th1-supportive state.

GATA-binding protein 3 (GATA3), a member of the GATA transcription factor family crucial for cellular development and differentiation, is normally expressed at low levels in mature neurons. However, its pathophysiological role in the brain remains poorly understood. Here, we report that GATA3 is involved in the mechanisms underlying chronic stress-induced depressive-like behaviors. Specifically, GATA3 expression was significantly increased in the hippocampal CA3 region of male mice exposed to established chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models of depression. Intra-CA3 infusion of K-7174, a GATA family inhibitor, or genetic knockdown of GATA3 in CA3 pyramidal neurons (PNs) protected against CSDS and CRS, exerting significant antidepressant-like effects. Conversely, overexpression of GATA3 in CA3 PNs induced depressive-like behaviors in male naïve mice. Mechanistically, GATA3 modulated depressive-like behaviors in male mice by regulating CA3 pyramidal neuronal activity and excitatory synaptic transmission. Our findings demonstrate a novel role for GATA3 in regulating depressive-like behaviors and suggest its potential as a promising target for antidepressant development.

Endothelial-to-mesenchymal transition (EndoMT), a process in which endothelial cells progressively differentiate into a mesenchymal phenotype, is a pivotal contributor to cardiac fibrotic remodelling and heart failure (HF) pathogenesis following ischaemic injury. In this study, poly(ADP-ribose) polymerase 1 (PARP1) was identified as a critical driver of EndoMT in ischaemic HF. Single-cell sequencing data indicated that compared with other cardiac cell types, cardiac endothelial cells highly express PARP1. PARP1 was upregulated in patients with dilated or ischaemic cardiomyopathy, as well as in patients with myocardial infarction who developed HF. Similarly, PARP1 upregulation was observed in vitro in EndoMT models induced by hypoxia or TGF-β1(Transforming Growth Factor Beta 1)/IL-1β (Interleukin-1β) and in vivo in cardiac endothelial cells from mice with ischaemic HF induced by permanent left anterior descending (LAD) artery ligation. Pharmacological inhibition and knockdown of PARP1 expression significantly inhibited EndoMT. Moreover, treatment with PARP1 inhibitors or endothelial-specific AAV-mediated delivery of PARP1 shRNA prevented ischaemia-induced EndoMT, fibrosis and cardiac dysfunction in mice. Mechanistically, PARP1 catalysed the poly(ADP-ribosyl)ation (PARylation) modification of four-and-a-half LIM domains protein 2 (FHL2), a key regulator of EndoMT. PARylation of FHL2 at residues Asp50, Glu63 and Asp77 promoted its nuclear retention, enhanced its interaction with β-catenin, and potentiated β-catenin transcriptional activity. Abrogating FHL2 PARylation via site-directed mutagenesis abolished the pro-EndoMT effects of PARP1. These findings establish endothelial PARP1 as a promising therapeutic target for EndoMT in ischaemic HF.

Triple-negative breast cancer (TNBC) is a clinically aggressive and molecularly heterogeneous subtype defined by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Chemotherapy remains the mainstay of treatment, but recent advances in immune checkpoint inhibitors, DNA damage response-targeted therapies, antibody-drug conjugates, and small-molecule inhibitors have expanded therapeutic options. Despite these developments, clinical outcomes are still limited by tumor heterogeneity, suboptimal biomarker selection, resistance, and treatment-related toxicity. In this review, we summarize current and emerging therapeutic strategies for TNBC with a focus on their underlying biological rationale. We highlight key approaches targeting DNA repair deficiency, immune regulation, oncogenic signaling pathways, and antigen-directed therapies, and discuss their clinical development and application. We also address the role of molecular subtyping and biomarkers in guiding treatment selection, as well as the challenges posed by resistance and limited durability of response. Overall, this review provides an updated overview of TNBC treatment strategies and discusses ongoing challenges and future directions toward more effective and individualized therapies.

Heart failure (HF) represents the final stage of cardiovascular disease progression, characterized by high morbidity and mortality. Pressure overload in HF activates the PI3K/AKT pathway, and prolonged activation leads to pathological cardiac hypertrophy. However, the mechanism underlying sustained PI3K/AKT activation in pressure overload-induced HF remains unclear. In this study, we demonstrate that miR-203 overexpression in transgenic mice counteracts cardiac dysfunction and pathological remodeling in HF, whereas miR-203 downregulation exacerbates HF. At the cellular level, miR-203 overexpression significantly reduces Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and injury, while miR-203 knockdown aggravates these effects. Mechanistically, miR-203 binds to the 3' untranslated region (3'UTR) of insulin-like growth factor binding protein 5 (IGFBP5) mRNA, inhibiting IGFBP5 protein expression, thereby suppressing PI3K/AKT signaling and mitigating cardiomyocyte hypertrophy. Furthermore, we demonstrate that fibronectin-1 (FN1) is a critical functional partner for IGFBP5, as knockdown of FN1 attenuates IGFBP5-induced PI3K/AKT activation and hypertrophy. This study is the first to elucidate the role and mechanism of miR-203 in regulating pressure overload-induced HF, offering a potential genetic tool for HF therapy.

Occipital neuralgia (ON) is a refractory chronic headache disorder characterized by paroxysmal shooting or stabbing pain in the posterior scalp, innervated by occipital nerves that originate from C2 and C3 dorsal root ganglion (DRG) neurons. Limited access to human DRG samples has impeded the understanding of the cellular and molecular mechanisms and the development of effective treatments for ON. We innovatively employed percutaneous full-endoscopic C2 ganglionectomy and subsequently performed single-nucleus RNA-sequencing (snRNA-seq) on C2 DRG from both ON patients and healthy controls. Somatostatin-expressing (SST⁺) neurons were selectively downregulated in patients with ON. Behavioral studies demonstrated that ablation of SST⁺ neurons induced pain, while optogenetic or chemogenetic activation of these neurons alleviated acute and chronic pain in mice. Altogether, this study provides new insights into the mechanisms underlying ON, revealing potential therapeutic targets for pain management.

G₁ to S phase transition 1 (GSPT1) represents a promising yet historically challenging therapeutic target for MYC-driven malignancies. Herein, we identified XYD113, a potent and highly selective GSPT1-targeting molecular glue degrader. XYD113 exhibits significant antiproliferative activity (IC₅₀ < 100 nM) against multiple MYC-overexpressing cancer cell lines (22Rv1, MV4-11, MOLM-16, Calu-1, HS-SY-II), and induces GSPT1 degradation in a dose- and time-dependent manner, with potency comparable to that of the clinical candidate MRT-2359. It also exhibits excellent selectivity without degrading common glutarimide analog substrates (such as SALL4, IKZF1/2/3, or CK1α). Mechanistically, XYD113 acts as a molecular glue to facilitate CRBN-GSPT1 ternary complex formation, mediating GSPT1 degradation via the UPS in a CRBN-dependent manner. Additionally, XYD113 demonstrates favorable stability in liver microsomes. Notably, XYD113 effectively downregulates the expression of genes critical for the initiation and progression of prostate cancer. In vivo, oral administration of XYD113 (5 mg/kg, daily for 21 days) significantly inhibited 22Rv1 xenograft growth (TGI = 46%) and showed a favorable safety profile in BALB/c-nude mice. Together, these findings highlight XYD113 as a promising therapeutic degrader worthy of further development for the treatment of MYC-driven cancers.