Acta Pharmaceutica Sinica B

Home Latest Articles

Latest Articles

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.
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.
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.
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).
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.
Site-specific PEGylation of proteins: Insights into structural and functional changes

Acta Pharmaceutica Sinica B. 2025, 15(12): 6253-6273.

Polyethylene glycol (PEG) is a polymer with different molecular weights formed by the polymerization of ethylene oxide monomers. Due to its ability to significantly reduce the immunogenicity of protein drugs and extend their half-life, as well as its high safety profile, it has been approved by the U.S. Food and Drug Administration (FDA) as the gold standard for delivering protein drugs. Although numerous PEGylated protein drugs have been marketed, the focus of research on PEGylated protein drugs has primarily been on reducing immunogenicity and extending in vivo circulation half-life. However, the understanding of how PEG modification affects the structure and function of proteins is still limited, with “activity” often being the sole criterion for evaluating changes in protein structure and function. A deeper exploration of the existence and interaction between PEG chains and proteins is of great significance for understanding the properties exhibited by PEGylated proteins. This review summarizes strategies for PEG site-specific modification of proteins, the interaction states between PEG and proteins, and the effects of PEG chains on protein spatial structure, solubility, activity, and thermal stability. It also summarizes the characterization techniques for PEG–protein interactions, aiming to predict or explain the functions of PEGylated protein drugs through the analysis of PEG–protein interactions.
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.
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.
Progress in peptide and protein therapeutics: Challenges and strategies

Acta Pharmaceutica Sinica B. 2025, 15(12): 6342-6381.

Peptide- and protein-based therapeutics offer realized and potential benefits to health, due to their potent bioactivity, high specificity, and favorable safety characteristics. However, their widespread clinical application is constrained by inherent limitations, including rapid enzymatic degradation, poor membrane permeability, and a reliance on parenteral administration, which reduces patient adherence. To overcome these challenges, extensive research has explored non-invasive delivery strategies, including topical, transdermal, and oral formulations. Despite promising advances in these delivery strategies, they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics, such as enzymatic degradation in the gastrointestinal tract, limited epithelial transport, and inherently low systemic bioavailability. This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy. It critically examines key challenges associated with various administration routes, including topical, transdermal, oral (including delivery targeting the brain), and others. Furthermore, it explores innovative strategies to enhance peptide and protein stability and bioavailability, including chemical modifications, enzyme inhibitors, penetration enhancers, physical delivery technologies, and advanced nanoparticulate formulations. Additionally, emerging trends in formulation optimization, regulatory considerations, and translational pathways for clinical implementation are discussed. By addressing these critical challenges and highlighting recent advances, this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy, and enhanced patient adherence, which is needed to fully realize the true potential of this class of therapeutics.

Previous 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 Next

Submission

Peer Review

Staff Login