Acta Pharmaceutica Sinica B

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Glutamine synthetase in astrocytes of the caudate and putamen is responsible for locomotor sensitization after nicotine exposure

Acta Pharmaceutica Sinica B. 2025, 15(12): 6399-6414.

Glutamine synthetase (GS) in astrocytes regulates glutamatergic neurotransmission by maintaining glutamate clearance in the brain. This study determined that GS in astrocytes of the caudate and putamen (CPu) regulates locomotor sensitization after repeated nicotine exposure. Nicotine increased phosphorylated c-Jun N-terminal kinase (pJNK) by stimulating α7 nicotinic acetylcholine receptors in cultured glioma C6 cells and primary astrocytes in a Ca²⁺-dependent manner. Active JNK phosphorylated metabotropic glutamate receptor 1a (mGluR1a) at the carboxyl terminus of glutathione S-transferase-tagged mGluR1a in vitro. Interference with the pJNK–mGluR1a interaction using the inhibitory peptide, Tat-mGluR1a-i (10 μmol/L), decreased the nicotine-induced increase in GS activity in glioma C6 cells and primary astrocytes. Similar results were obtained by bilateral intra-CPu infusion of the inhibitory peptide (2 nmol/side). Inhibition of GS activity by bilateral intra-CPu infusion of methionine sulfoximine (50 nmol/side) decreased the repeated nicotine-induced increase in locomotor activity. These findings suggest that astrocytes in the CPu upregulate locomotor sensitization by activating GS via the pJNK–mGluR1a interaction, which is linked to α7 nicotinic acetylcholine receptors in response to nicotine.
MYD88 regulates the intercellular crosstalk landscape in MASH liver against metaflammation and metabolic disorder

Acta Pharmaceutica Sinica B. 2025, 15(12): 6415-6429.

Metabolic dysfunction-associated steatohepatitis (MASH) is the main cause of end-stage liver disease. We analyzed cell communication via ligand–receptor signaling at the single-cell level to elucidate cell-specific responses and spatial zonation in MASH. We screened and validated Myd88 hyperexpression in liver sinusoidal endothelial cells and liver capsular macrophages (LCM). We showed that Myd88 levels in the periportal endothelial cells of mice with MASH were higher than those in healthy controls, correlating significantly with dysregulation of capillarization markers in vivo. Moreover, Myd88⁺ LCM is a primary source of diverse signaling ligands involved in inflammatory cell recruitment during diet-induced MASH. CD24-Fc bound to the inhibitory receptor SIGLECG to significantly enhance SHP1 binding to MYD88, thereby inhibiting its activation and contributing to the restoration of immune-inflammatory homeostasis in the livers of diet-induced MASH mice. CD24-Fc improved amylin liver nonalcoholic steatohepatitis-induced MASH, which was partly abolished by AAV6-mediated Myd88 knockout in vivo. These findings underscore the central role of MYD88 in MASH etiology, and the specific targeting of MYD88 in liver sinusoidal endothelial cells and LCM may be a potential therapeutic approach to slow the progression of MASH.
Elevated SNHG15 empowers keratinocytes hyperproliferation through activation of STAT3/Cyclin D1 axis in psoriasis

Acta Pharmaceutica Sinica B. 2025, 15(12): 6430-6443.

Psoriasis is a common inflammatory skin disease with characterization of epidermal hyperplasia and sustained skin inflammation. Long noncoding RNAs (lncRNAs), which contain more than 200 nucleotide-long transcripts, are emerging as the crux of epigenetic regulators in multiple biological processes and diseases. However, how lncRNAs contribute to the etiology of psoriasis remains to be elucidated. For the first time, this study revealed that SNHG15, which was elevated in cytokines-stimulated keratinocytes and psoriasis lesions, promoted keratinocytes hyperproliferation. Mechanistically, SNHG15 fueled epithelial pathology through activation of STAT3/Cyclin D1 axis. Intriguingly, activation of STAT3 enhanced SNHG15 transcription to form a positive feed-back modulatory loop and consequently augmented the skin lesions in psoriasis. Furthermore, knock down the expression of SNHG15 can counteract the IMQ-induced keratinocytes hyperproliferation in vivo. Taken together, our findings uncover that SNHG15 facilitates epidermal hyperplasia via STAT3/Cyclin D1 axis, which might provide a novel therapeutic avenue for psoriasis treatment.
The cytoskeletal protein smoothelin maintains homologous recombination repair by stabilizing RAD51 in an HUWE1-dependent manner in colorectal cancer

Acta Pharmaceutica Sinica B. 2025, 15(12): 6444-6460.

Dysregulation of cytoskeletal proteins has been found in response to DNA damage stress, yet the functional role of cytoskeletal proteins in DNA repair remained unexplored. Here, we found that DNA-damaging agents induced substantial upregulation of smooth muscle-specific cytoskeletal protein smoothelin (SMTN) in colorectal cancer (CRC) cells. Silencing SMTN abrogated G2/M arrest, exacerbated DNA damage, and markedly enhanced the chemosensitivity of CRC cells to various DNA-damaging agents. Notably, SMTN could rapidly accumulate at DNA damage sites within 1 min after laser irradiation, which was indispensable for the initiation of homologous recombination (HR) repair. Mechanistically, SMTN stabilized RAD51 by disrupting its interaction with its E3 ubiquitin ligase HUWE1, thereby maintaining the process of HR repair. To explore the therapeutic role of SMTN, customized cell membrane infused biomimetic liposomes were constructed to ensure rapid delivery of SMTN siRNA specifically into HCT-116 cells, yielding significantly enhanced anti-cancer effects of irinotecan and fuzuloparib both in vitro and in vivo. To summarize, our findings revealed a novel function of SMTN in DNA damage repair and provided a therapeutic strategy of targeting SMTN to enhance the efficacy of DNA damage agents.
THBru ameliorates atherosclerosis by inhibiting endothelial ferroptosis via regulation of the super-enhancer-associated ABCC1

Acta Pharmaceutica Sinica B. 2025, 15(12): 6461-6477.

Atherosclerosis is a chronic vascular disease closely associated with endothelial dysfunction. Ferroptosis, a major factor in endothelial dysfunction, plays a pivotal role in the progression of atherosclerosis. The development of drugs targeting endothelial ferroptosis offers a potential therapeutic approach for atherosclerosis. This study aimed to assess the potential impact of tetrahydroberberrubine (THBru) on atherosclerosis and unravel its molecular mechanism underlying endothelial protection. Our results demonstrated that THBru significantly reduced plaque formation in the aortas of atherosclerotic mice. Through transcriptome sequencing and further verification, we observed that THBru mitigated endothelial ferroptosis in atherosclerosis by enhancing glutathione homeostasis and decreasing reactive oxygen species (ROS) accumulation. Mechanistically, bioinformatic analysis demonstrated that THBru reduced the expression of the super-enhancer (SE) regulatory gene ATP-binding cassette subfamily C member 1 (ABCC1). The transcription factor BTB and CNC homology 1 (BACH1) was responsible for ABCC1 transcription by binding to its SE (ABCC1-SE), whereas THBru effectively inhibited the activity of ABCC1-SE. Furthermore, THBru promoted adenosine monophosphate-activated protein kinase (AMPK) activation, thereby negatively regulating BACH1 and the downstream ABCC1/ferroptosis signaling pathway. Collectively, these findings highlight THBru as a promising candidate for treating atherosclerosis, featuring a novel mechanism that inhibits endothelial ferroptosis through the AMPK/BACH1 axis to regulate ABCC1-SE.
IGF2BP1 positively regulates CircOGDH accumulation in hypoxia induced stress granules

Acta Pharmaceutica Sinica B. 2025, 15(12): 6478-6494.

The ischemic penumbra is critical in acute ischemic stroke (AIS) treatment, yet the regulation of precise RNA modification pathways remains unclear. Using a mouse model of ischemic stroke and human postmortem brain samples, we demonstrate that N⁶-methyladenosine (m⁶A) levels are elevated in neurons within the ischemic penumbra. Notably, m⁶A modifications by m⁶A reader protein IGF2BP1 were enriched on penumbra related circular RNA derived from oxoglutarate dehydrogenase (CircOGDH). IGF2BP1 stabilizes CircOGDH by recruiting it to stress granules, maintaining high expression in the ischemic penumbra. Knockdown of IGF2BP1 reduced CircOGDH stability and decreased neuronal apoptosis under hypoxic conditions, suggesting a protective role. Igf2bp1 knockdown also preserved synaptic integrity in MCAO mice, with increased expression of synaptic markers and improved synaptic morphology. Importantly, Igf2bp1 knockdown significantly reduced penumbra volume compared to CircOGDH inhibition alone. These findings highlight IGF2BP1 as a promising therapeutic target for modulating penumbra-related RNA expression and promoting recovery in AIS.
Undulanoids A-D: Unexpected sesterterpenoids as potent S100A8/A9 complex inhibitors for psoriasis treatment

Acta Pharmaceutica Sinica B. 2025, 15(12): 6495-6509.

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and remains a challenge in its management. Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family, S100A8 and S100A9, in keratinocytes is a promising strategy for future therapeutic approaches. Undulanoids A-D (1-4), four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers, including three all-carbon quaternary centers, two quaternary carbon centers at the bridgehead, and a 1,4,11-trimethyltricyclo[5.3.1.0^4,11]undecane fragment, were isolated from Aspergillus undulatus. Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction. Strikingly, undulanoid B (2), the most promising lead compound, inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways. Furthermore, reverse target prediction, cellular thermal shift assay, and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation. As the pioneering S100A8/A9 complex and inhibit its secretion. Moreover, compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation. As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex, this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.
Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy

Acta Pharmaceutica Sinica B. 2025, 15(12): 6510-6528.

Degrader–antibody conjugates (DACs) represent a promising drug modality for targeting hematological malignancy, but still lack rational design frameworks. Here, we show the strategies of reasonable antibody-degrader compatibility and degradation tail-derived conjugatability through a systematic exploration. Inspired by the success of IKZF1/3 degraders, we sought to explore the potential of cereblon E3 ligase modulators (CELMoDs) in constructing novel conjugates. By combining a modular library with neo-substrate screening and further conjugatable derivation, I034 was identified, a potent CELMoD payload with picomolar degradation activity and antiproliferative effects. Through linker chemistry, I034-based DACs were constructed and demonstrated superior efficacy and safety compared to auristatin-based conjugates both in vitro and in vivo, with the CD38-targeting Dara-VA-I034 achieving complete tumor eradication at low doses. Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates, highlighting the need for compatibility between payloads and antigens. These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies.
Discovery of peptidomimetic inhibitors of CREB/CBP by targeting hydrophobic grooves on the surface of the CBP KIX domain

Acta Pharmaceutica Sinica B. 2025, 15(12): 6529-6545.

Cyclic AMP-response element binding protein (CREB), a downstream transcription factor of multiple signaling pathways, is overexpressed in many different types of cancers. Thus, targeting CREB has great potential for the development of antitumor agents. Peptidic foldamers have emerged as a powerful tool to disrupt disease-related protein–protein interactions (PPIs) with chemodiversity and high stability towards enzymatic degradation. Herein, we harnessed several hydrophobic groups of helical sulfonyl-γ-AApeptide foldamer targeting the hydrophobic grooves on the surface of the KIX domain of CREB binding protein (CBP), to disrupt CREB/CBP PPI. We showed that several stapled sulfonyl-γ-AApeptides could suppress CREB-mediated gene transcription and exhibit effective antiproliferative activity in cell-based assays and demonstrate its potency in inhibiting tumor growth in vivo. Our studies suggest that sulfonyl-γ-AApeptides as a class of helical foldamer could mimic the helical kinase-inducible activation domain of CREB (KID) to target the hydrophobic grooves on the surface of CBP KIX domain, and thereby inhibiting KIX–KID interaction, which provides a new strategy for the development of antitumor agent by targeting PPIs involving intrinsically disordered proteins (IDPs).
Key imidazolyl groups that induce phenylalanine flipping enhance the efficacy of oral BRD9 inhibitors for AML treatment

Acta Pharmaceutica Sinica B. 2025, 15(12): 6546-6570.

The bromodomain-containing protein 9 (BRD9) is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF. BRD9 has emerged as a potential target for anticancer drugs, particularly in the treatment of acute myeloid leukemia (AML). Herein, we reported 10m (Y22073) and 10t as new BRD9 selective bromodomain inhibitors. Crystallographic studies revealed that the key active imidazolyl group discovered from structure-activity relationship (SAR) can induce Phe163 flipping and significantly enhance the cellular potency of the compounds, making 10m the first BRD9 selective inhibitor with significant cellular activity against AML cells. We also validated the critical role of imidazolyl groups by modifying existing BRD9 inhibitors. The representative compounds 10m and 10t demonstrated potent binding affinity, outstanding selectivity toward BRD9 bromodomain, and significantly inhibited the proliferation of AML cell lines. 10m also showed good metabolic stability, solubility and pharmacokinetic properties. Additionally, oral administration of compounds 10m and 10t exhibited potent anti-tumor efficacy in the MV4-11 xenograft mouse model. The potent, selective, and orally available BRD9 bromodomain inhibitors may address the challenges of weak cellular activity and limited phenotypic efficacy faced by BRD9 inhibitors, and serve as new lead compounds for the development of anticancer agents for the treatment of AML.

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