Acta Pharmaceutica Sinica B

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Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders

Wenbo Feng, Qingtong Zhou, Ming-Wei Wang

Acta Pharmaceutica Sinica B. 2026, 16(8): 5016-5033.

The melanocortin-4 receptor (MC4R) is a key regulator of energy balance and a potential target for weight management. Early drug discovery endeavors were hindered by incomplete understanding of its signal transduction mechanisms and broad activation of Gs pathways. Recent advances indicate that MC4R elicits multiple intracellular responses, with Gq/₁₁ signaling in the paraventricular nucleus (PVN) neurons playing a central role in appetite suppression. High-resolution cryo-electron microscopy structures of MC4R, such as the setmelanotide-MC4R-Gq complex reported here, provide valuable insights into ligand binding, receptor activation, and biased signaling, thereby enabling the design of more selective agonists with improved safety profiles. Combination therapies targeting MC4R alongside glucagon-like peptide-1 mimetics and other agents regulating metabolic pathways have shown promise to enhance weight loss. MC4R modulators are also implicated in treating other disorders, including melanocortin signaling dysfunction. These progresses call for renewed efforts in developing the next-generation MC4R-based therapies against metabolic diseases.
DeepHalo: Deep learning-powered exploration of halogenated metabolites uncovering antibacterial depsipeptides

Acta Pharmaceutica Sinica B. 2026, 16(8): 5034-5052.

In the omics era, confident high-throughput analytical tools are crucial for the efficient identification of metabolites. Here, we present DeepHalo, a deep learning-integrated and hierarchically optimized workflow designed for high-throughput exploration of halogenated metabolites from high-resolution mass spectrometry-based metabolomics. DeepHalo leverages deep learning models combined with a comprehensive scoring to enhance the reliability of halogen predictions. It integrates PyOpenMS for fast isotope pattern detection and incorporates a halogen-based dereplication algorithm with GNPS molecular networking to efficiently exploit and annotate halogenates from complex biological matrices. To validate its performance, DeepHalo was applied to explore halogenated metabolites from 1296 microbial culture crudes, leading to the discovery of six families of structurally diverse halogenated molecules. This included a new class of cyclic depsipeptides, aglomycins A‒E, featuring rare 3-chloroanthranilic acid and/or epoxyvaline blocks. Additionally, a plausible biosynthetic pathway of aglomycins was proposed through bioinformatics analyses and targeted gene knockout experiments. Bioassays revealed that aglomycin A exhibits synergistic antibacterial activity with linezolid against vancomycin-resistant Enterococcus faecium (VRE) both in vitro and in vivo. We envision that DeepHalo, a user-friendly standalone executable freely available at https://github.com/xieyying/deephalo/releases/tag/DeepHalo_V1.0.0, will become a powerful tool for accelerating the discovery of halogenated “dark matter”.
A novel machine learning framework-based rapid screening of ionizable lipids in LNPs for highly-efficient mRNA expression

Acta Pharmaceutica Sinica B. 2026, 16(8): 5053-5069.

Ionizable lipids are a pivotal component for lipid nanoparticles (LNPs) to optimize mRNA expression to fulfill the broad demands of various mRNA therapeutics. Traditionally, the screening of ionizable lipids needs extensive synthetic labor and stringent in vivo efficacy evaluation, which was often time-consuming, costly, and characterized by a lower success rate. Hence, we pioneered a machine-learning framework named Lipid with Artificial Intelligence (LipidAI) to evaluate the novel ionizable lipids rapidly. In this framework, the Methyl Tail Augmentation (MTA) strategy was first developed to triple the data by precisely adjusting the methyl groups on lipid tail chains. This ground-breaking approach compensated for data paucity in ionizable lipids libraries from the previous research and boosts model accuracy. Subsequently, the Ensemble Stacking Learning (ESL) algorithm was exploited to integrate multiple learning algorithms to surpass the predictive accuracy of a single algorithm used in former studies. Finally, we found that the predicted results of LipidAI were highly consistent with the actual data according to the in vivo expression of Luc-mRNA. Overall, this study highlights the remarkable potential of LipidAI in the rapid screening of ionizable lipids, adeptly avoiding the inherent drawbacks of traditional ionizable lipids development and thereby boosting the progress of LNP-based mRNA nano-drugs.
H2AC19 promotes lung adenocarcinoma progression via p300/EGR1/MMP-1-mediated angiogenesis

Fuwen Zuo, Jinlong Yu, Tong Liu, Xiaorui Liu, Jilong Yin, Pengzhong Ding, Yuhan Pang, Zhengdong Luo, Xiaofeng Wang, Ling Guo, Yirong Zhang, Shuang Qi, Lutao Du, Ziying Wang, Fan Yi, Xiaoshi Zhang

Acta Pharmaceutica Sinica B. 2026, 16(8): 5070-5085.

Angiogenesis is a hallmark of lung adenocarcinoma (LUAD) and a leading cause of mortality. Identifying potential therapeutic targets that modulate this process is of critical clinical importance. Here, we established a 12-gene risk-scoring model through bioinformatics screening and systematically delineated the molecular function of H2AC19, a previously poorly understood histone variant within this signature. Analysis of human LUAD specimens revealed elevated H2AC19 expression, which correlated positively with angiogenesis markers and advanced clinical stage and negatively with patient prognosis. Functional validation using CRISPR/Cas9 in patient-derived organoids (PDOs), in vitro cell models and in vivo xenografts demonstrated that H2AC19 promotes angiogenesis and tumor growth. Mechanistically, H2AC19 recruits p300 through its amino acid residues 24-88 to specifically augment H3K27 acetylation at the EGR1 promoter region, thereby triggering EGR1 transcriptional activation and subsequently promoting MMP-1-driven angiogenesis and progression of LUAD. Furthermore, we evaluated the therapeutic potential of lipid nanoparticles (LNP)-encapsulated siRNA targeting H2AC19, which significantly suppressed angiogenesis and LUAD progression. Collectively, our findings establish a critical role for H2AC19 in governing angiogenesis and highlight its potential as a promising therapeutic target for LUAD.
Progranulin drives acetaminophen-induced acute liver injury by limiting hepatic recruitment of eosinophils via suppressing interleukin-33 expression

Acta Pharmaceutica Sinica B. 2026, 16(8): 5086-5107.

Drug-induced liver injury (DILI), particularly acetaminophen (APAP)-induced acute liver injury (ALI), is the leading cause of acute liver failure. Progranulin (PGRN) is a multifunctional glycoprotein. However, the role of PGRN in APAP-induced ALI remains unknown. Here, we found that PGRN serum concentration increased and correlated with disease severity in the patients with APAP overdose. Mice with PGRN deficiency were protected from APAP-induced ALI or concanavalin A (ConA)-induced ALI. They exhibited substantially increased hepatic recruitment of eosinophils, which depended on up-regulated IL-33 that was primarily released from liver sinusoidal endothelial cells (LSECs). Moreover, treatment of mice with blocking PGRN antibody could prophylactically and therapeutically treat APAP- or ConA-induced ALI, while injection of recombinant PGRN protein enhanced APAP-induced liver damage and worsened survival. Mechanistically, PGRN inhibited APAP-induced IL-33 expression in LSECs by dampening the activation of AMP-activated protein kinase (AMPK)-forkhead box O3 (FOXO3) signaling pathway. Therefore, PGRN should be considered as a new biomarker and potential therapeutic target to treat DILI.
Metabolic-epigenetic reprogramming via the PLOD1-PFKP axis drives cisplatin resistance in HNSCC

Acta Pharmaceutica Sinica B. 2026, 16(8): 5108-5130.

Cisplatin remains a cornerstone of treatment for head and neck squamous cell carcinoma (HNSCC), yet its therapeutic efficacy is often undermined by acquired resistance. Here, we identify the PLOD1-PFKP-glycolysis axis as a central driver of cisplatin resistance. PLOD1 is significantly upregulated in cisplatin-resistant tumors and correlates with poor prognosis. Mechanistically, PLOD1 stabilizes the glycolytic enzyme PFKP by promoting its AKT-mediated phosphorylation at serine 386 via the HSP90-AKT complex, thereby enhancing glycolytic flux. This metabolic reprogramming facilitates stem-like properties and sustains epithelial-mesenchymal transition (EMT). Furthermore, increased intracellular acetyl-CoA levels driven by this axis promote histone H3K27 acetylation at the TGFBR2 promoter, thereby activating TGF-β signaling. Genetic depletion or nanoparticle-mediated silencing of PLOD1 reverses EMT and stemness features, restores cisplatin sensitivity, and impairs tumor growth and metastasis in vivo. These findings reveal a PLOD1-PFKP-glycolysis axis as the principal driver of cisplatin resistance, which coordinates metabolic and epigenetic alterations to promote tumor plasticity. Targeting this axis offers a promising strategy to overcome chemoresistance in HNSCC.
CDK9 inhibition sensitizes intrinsically resistant BRAFV⁶⁰⁰E mutant colorectal cancer to BRAF inhibitors

Acta Pharmaceutica Sinica B. 2026, 16(8): 5131-5147.

Recently, the BRAF inhibitor (Encorafenib) in combination with Cetuximab and mFOLFOX6 has been approved for the treatment of metastatic CRC (mCRC) patients with BRAF V⁶⁰⁰E mutation in the first line. However, intrinsic resistance to BRAFi still limits its therapeutic efficacy, and the clinical response is only ∼5%. One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may yield synergistic antitumor efficacy and overcome drug resistance. Herein, CDK9 inhibitors (CDK9i) were identified as candidate synergistic agents through kinase library-based high-throughput screening (HTS) and RNA sequencing. CDK9i synergistically sensitizes the therapeutic efficacy of BRAFi (as well as inhibitors of well-known downstream effector of BRAF, MEK and ERK) in multiple intrinsically resistant CRC models. Notably, CDK9i in combination with BRAFi also resulted in an enhanced therapeutic response in chemo-resistant CRC cells and PDOs. Taken together, CDK9 inhibition overcomes intrinsic resistance to BRAFi monotherapy, and targeting CDK9-mediated transcriptional elongation appears to be a promising and tolerable sensitization strategy for BRAFi-based treatment in mCRC, even in chemo-resistant mCRC.
Novel circUnc79 regulates morphine-induced reward memory via the miR-149-3p/EAAT2 axis and glutamatergic plasticity

Acta Pharmaceutica Sinica B. 2026, 16(8): 5148-5167.

Opioid addiction is driven by maladaptive reward memory, yet its molecular underpinnings remain poorly understood. Circular RNAs (circRNAs) have emerged as key regulators of neuroplasticity, but their roles in addiction-related memory remain unclear. Here, we identify circUnc79, a neuron-enriched and synaptically localized circRNA, as a critical modulator of morphine reward memory in the medial prefrontal cortex (mPFC). In the morphine-induced conditioned place preference (CPP) model, circUnc79 expression is dynamically downregulated during cue-induced memory retrieval. Gain- and loss-of-function experiments demonstrate that circUnc79 bidirectionally regulates the acquisition and persistence of morphine reward memory, without affecting locomotion, anxiety-like behavior, social interaction, or sucrose reward. Mechanistically, circUnc79 acts as a competing endogenous RNA for miR-149-3p, thereby relieving its repression of excitatory amino acid transporter 2 (EAAT2, encoded by Slc1a2). Elevated neuronal EAAT2 enhances presynaptic glutamate reuptake and recycling, supporting reward memory encoding. Manipulation of miR-149-3p produces opposite behavioral and synaptic effects, supporting the functional relevance of this regulatory axis. These findings reveal a circUnc79/miR-149-3p/EAAT2 pathway that regulates synaptic plasticity underlying opioid reward memory and highlight circUnc79 as a potential therapeutic target for opioid use disorders.
Exendin-4 alleviates anxiety-like behaviors in chronic restraint stress mice via regulating BLA GLP-1R/BDNF signaling

Acta Pharmaceutica Sinica B. 2026, 16(8): 5168-5182.

Clinical studies have suggested that exendin-4 (Ex-4) exhibits therapeutic potential for anxiety disorders, yet the molecular mechanisms underlying its efficacy remain largely unclear. Our study demonstrates that Ex-4 at specific doses ameliorates anxiety-like behaviors in mice. Mechanistically, Ex-4 could cross the blood-brain barrier and enter the central nervous system, where it exerts anxiolytic effects by activating glucagon-like peptide-1 receptor (GLP-1R) in the basolateral amygdala (BLA). Anterior dorsal bed nucleus of the stria terminalis (adBNST) as a downstream projection target of BLA neurons. Chemogenomic inhibition of the BLA-adBNST circuit induced anxiety-like phenotypes, which were rescued by Ex-4 treatment. Brain-derived neurotrophic factor (BDNF), a critical neurotrophin implicated in neuropsychiatric disorders including anxiety and depression, was functionally interrogated in this pathway. Furthermore, conditional knockdown of Bdnf in the BLA-adBNST circuit abolished the anxiolytic effects of Ex-4, indicating that the activation of GLP-1R in BLA neurons drives BDNF release into adBNST to mitigate anxiety. Taken together, these studies identify a central mechanism whereby Ex-4 attenuates anxiety-like behaviors by promoting BDNF release in the BLA-adBNST circuit.
Loss of TET2 sulfhydration results in destabilization of TET2 and down-regulation of the immune response in melanoma

Acta Pharmaceutica Sinica B. 2026, 16(8): 5183-5199.

Loss of TET2 protein leads to reduced DNA 5-hydroxymethylation (5-hmC), a key epigenetic alteration in melanoma, yet the regulatory mechanism governing TET2 stability remains unclear. Here, TET2 sulfhydration was analyzed in clinical melanoma samples, with sulfhydration sites identified by mass spectrometry, and the effects of active sulfur on TET2 stability, catalytic activity, and global 5-hmC assessed in melanoma cells. TET2 sulfhydration was significantly depleted in melanoma and further reduced in advanced stages. The cysteine-rich zinc finger domain at C1186/1202 was identified as the key sulfhydration site, which is essential for maintaining TET2 stability and enzymatic activity. Active sulfur restored TET2 sulfhydration, up-regulated TET2 protein, and reprogrammed global DNA hydroxymethylation. Notably, active sulfur synergized with anti-PD-1 therapy by enhancing IFN-γ-induced Th1-type chemokine and MHC-I expression in melanoma cells, thereby boosting CD8⁺ T-cell-mediated immune responses. These findings demonstrate that TET2 sulfhydration at C1186/1202 is a crucial post-translational modification for TET2 stability and function, playing a key role in epigenetic regulation and antitumor immunity, and highlight the immunoadjuvant potential of reactive sulfur species in melanoma immunotherapy.

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