Acta Pharmaceutica Sinica B

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Palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis: A new target for anti-myocardial fibrosis

Xuewen Yang, Yanwei Zhang, Xiaoping Leng, Yanying Wang, Manyu Gong, Dongping Liu, Haodong Li, Zhiyuan Du, Zhuo Wang, Lina Xuan, Ting Zhang, Han Sun, Xiyang Zhang, Jie Liu, Tong Liu, Tiantian Gong, Zhengyang Li, Shengqi Liang, Lihua Sun, Lei Jiao, Baofeng Yang, Ying Zhang

Acta Pharmaceutica Sinica B. 2025, 15(9): 4789-4806.

Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.
Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer's disease

Anže Meden, Neža Žnidaršič, Damijan Knez, Yuanyuan Wang, Ziwei Xu, Huajing Yang, Weiting Zhang, Anja Pišlar, Andrej Perdih, Simona Kranjc Brezar, Neža Grgurevič, Stane Pajk, Haopeng Sun, Stanislav Gobec

Acta Pharmaceutica Sinica B. 2025, 15(9): 4807-4828.

The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α₂-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α₂-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.
Yeast-two-hybrid based high-throughput screening to discover SARS-CoV-2 fusion inhibitors by targeting the HR1/HR2 interaction

Acta Pharmaceutica Sinica B. 2025, 15(9): 4829-4843.

The continuous emergence of SARS-CoV-2 variants as well as other potential future coronavirus has challenged the effectiveness of current COVID-19 vaccines. Therefore, there remains a need for alternative antivirals that target processes less susceptible to mutations, such as the formation of six-helix bundle (6-HB) during the viral fusion step of host cell entry. In this study, a novel high-throughput screening (HTS) assay employing a yeast-two-hybrid (Y2H) system was established to identify inhibitors of HR1/HR2 interaction. The compound IMB-9C, which achieved single-digit micromolar inhibition of SARS-CoV-2 and its Omicron variants with low cytotoxicity, was selected. IMB-9C effectively blocks the HR1/HR2 interaction in vitro and inhibits SARS-CoV-2-S-mediated cell-cell fusion. It binds to both HR1 and HR2 through non-covalent interaction and influences the secondary structure of HR1/HR2 complex. In addition, virtual docking and site-mutagenesis results suggest that amino acid residues A930, I931, K933, T941, and L945 are critical for IMB-9C binding to HR1. Collectively, in this study, we have developed a novel screening method for HR1/HR2 interaction inhibitors and identified IMB-9C as a potential antiviral small molecule against COVID-19 and its variants.
Discovery of powerful multifaceted antioxidant for combating oxidative stress associated with neurodegenerative disorders

Acta Pharmaceutica Sinica B. 2025, 15(9): 4844-4871.

Amidst the tangled web of neurons, antioxidants stand as silent sentinels, shielding the delicate threads from the raging storm of oxidative stress in the realm of neurological affliction. Herein, we showcased an innovative design strategy to develop a novel powerful antioxidant small molecule (AOX), designed with the synergistic integration of EGCG (epigallocatechin gallate), gallic acid, and coupled with the metal-chelating capabilities of 8-hydroxy quinoline functional moieties that exhibit multifunctional activity in combating oxidative stress via activating the anti-oxidative, anti-apoptotic and anti-inflammatory activity, showcasing the potential for a transformative impact in neuroprotection from oxidative insults. Our work addresses oxidative stress in neuronal systems by providing a thorough examination of oxidative stress caused by hydrogen peroxide in PC12 cell line-derived neurons by shedding light on the antioxidative mechanisms orchestrated by our novel small molecule. Particularly our designed molecule (AOX) provides neuroprotection by mitigating mitochondrial impairment and activating the Nrf2/ARE (nuclear factor erythroid 2-related factor 2/antioxidant response element) pathway and it also demonstrates remarkable resilience against neuroinflammation, as evidenced by minimal alterations in neuroinflammatory markers such as GFAP, IBA1, and S100β in a transient bilateral common carotid artery occlusion (tBCCAO) ischemic stroke model.
The toxic components, toxicological mechanism and effective antidote for Gelsemium elegans poisoning

Acta Pharmaceutica Sinica B. 2025, 15(9): 4872-4885.

Gelsemium elegans (G. elegans) is an extremely poisonous plant that is widely distributed in southern China and southeastern Asia. G. elegans poisoning events occur frequently in southern China, and are therefore an urgent public health problem requiring multidisciplinary action. However, the toxic components and toxicological mechanisms remain unclear. Here, we describe a systematic investigation on the toxic components of G. elegans, resulting in the isolation and identification of 120 alkaloids. Based on acute toxicity screening, the structure-toxicity relationship of Gelsemium alkaloids was proposed for the first time. Moreover, gelsedine- and humantenine-type alkaloids were detected in the clinical blood sample, and were confirmed to be causative in the poisoning. The most toxic compound, gelsenicine (1), had selective inhibitory effects toward ventral respiratory group (VRG) neurons in the medulla, which is the main brain region controlling respiration in the central nervous system. Gelsenicine (1) strongly inhibited the firing of action potentials in VRG neurons through its ability to stimulate GABAA receptors, the main receptors involved in inhibitory neurotransmission. Application of GABAA receptor antagonists successively reversed action potential firing in gelsenicine (1)-treated VRG neurons. Importantly, the GABAA receptor antagonists securinine and flumazenil significantly increased the survival of poisoned animals. Our findings provide insight into the components and mechanisms of G. elegans toxicity, and should assist the development of effective emergency treatments for G. elegans poisoning.
Activatable PROTAC nanoassembly for photodynamic PTP1B proteolysis enhances glioblastoma immunotherapy

Acta Pharmaceutica Sinica B. 2025, 15(9): 4886-4899.

In light of the burgeoning successes of cancer immunotherapy, glioblastoma (GBM) remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity. Thus, identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge. Here we describe photodynamic protein tyrosine phosphatase 1B (PTP1B) proteolysis mediated by a proteolysis-targeting chimera (PROTAC) nanoassembly. The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B (Cat B)-cleavable peptide, which spontaneously forms nanoassemblies due to intermolecular π-π stacking interactions. In GBM models, PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood-brain barrier (BBB), triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage. Upon laser irradiation, photodynamic therapy (PDT) synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death (ICD) in tumor cells. Subsequently, persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers, reinvigorating their functionality. These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cell-mediated antitumor immunity as well as protective immunity, completely eradicating the primary GBM and preventing its recurrence. Overall, our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.
Intercellular communication interference through energy metabolism-related exosome secretion inhibition for liver fibrosis treatment

Acta Pharmaceutica Sinica B. 2025, 15(9): 4900-4916.

As activated hepatic stellate cells (aHSCs) play a central role in fibrogenesis, they have become key target cells for anti-fibrotic treatment. Nevertheless, the therapeutic efficiency is constrained by the exosomes they secrete, which are linked to energy metabolism and continuously stimulate the activation of neighboring quiescent hepatic stellate cells (qHSCs). Herein, an intercellular communication interference strategy is designed utilizing paeoniflorin (PF) loaded and hyaluronic acid (HA) coated copper-doped ZIF-8 (PF@HA-Cu/ZIF-8, PF@HCZ) to reduce energy-related exosome secretion from aHSCs, thus preserving neighboring qHSCs in a quiescent state. Simultaneously, the released copper and zinc ions disrupt key enzymes involved in glycolysis to reduce bioenergy synthesis in aHSCs, thereby promoting the reversion of aHSCs to a quiescent state and further decreasing exosome secretion. Therefore, PF@HCZ can effectively sustain both aHSCs and qHSCs in a metabolically dormant state to ultimately alleviate liver fibrosis. The study provides an enlightening strategy for interrupting exosome-mediated intercellular communication and remodeling the energy metabolic status of HSCs with boosted antifibrogenic activity.
A novel dual-targeting strategy of nanobody-driven protein corona modulation for glioma therapy

Acta Pharmaceutica Sinica B. 2025, 15(9): 4917-4931.

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a “Hitchhiking Effect” mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.
KRAS mutant colon cancer-targeted induction of ferroptosis via photocatalytic activation of BiVO₄-embedded silica nano with cascadic downregulation of GPX4/xCT axis

Yixin Jiang, Ratchapol Jenjob, Dahee Ryu, Zheyu Shen, Su-Geun Yang

Acta Pharmaceutica Sinica B. 2025, 15(9): 4932-4944.

Kirsten rat sarcoma virus (KRAS) is a common oncogene in human cancers. Approximately 40% of the patients diagnosed with colorectal cancer (CRC) have KRAS mutations that exhibit strong resistance to targeted molecular therapy and EGFR antibody treatment. In this study, we present photocatalytic silica nanoparticles (A6-FS/BiVO₄ DMSNs) for targeted therapy of KRAS mutant CRC with the induction of cascadic ferroptosis events. Dendritic mesoporous silica nanoparticles (DMSNs) were impregnated with photocatalytic BiVO₄, loaded with ferroptotic agents (benzoyl ferrocene: B and sorafenib: S), and encoded with CD44-targeting A6 peptides. For the targeting design, we observed CD44 overexpression in KRAS mutant CRC cells using CPTAC data analysis. Upon laser irradiation, A6-FS/BiVO₄ DMSNs generate electron-hole pairs (e⁻/h⁺), which produce hydroxyl radical (OH·) and superoxide anions (O₂·⁻). Laser irradiation simultaneously initiates the dissociation of iron (Fe²⁺) from benzoyl ferrocene and the release of sorafenib. This cascade induces ferroptosis in KRAS mutant CRC cells, especially under conditional inhibition of redox-regulating proteins (cystine/glutamate antiporter and glutathione peroxidase 4), and significantly inhibits tumor growth in a KRAS mutant CRC xenograft animal model.
Photodynamic enhancement of PROTAC prodrug activation in hypoxic tumors

Acta Pharmaceutica Sinica B. 2025, 15(9): 4945-4960.

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising therapeutic strategy for targeted protein degradation. However, the clinical application of PROTACs may be hindered by off-target toxicity resulting from non-tissue-specific protein degradation and ingenious prodrug strategies may open new avenues to addressing this concern. Herein, we propose a light-induced positive feedback strategy to use photodynamic therapy (PDT) to improve the activation efficiency of PROTAC prodrugs, monitor PROTAC release, and combine PROTAC to induce tumor cell apoptosis. In the hypoxic tumor microenvironment, the azo bond in AZO-PRO selectively cleaves, triggering the release of the potent protein degrader PRO and the multifunctional photosensitizer. Once activated, the fluoresce signal of the photosensitizer dramatically recovers, allowing monitoring of prodrug activation. Additionally, upon irradicating the tumor site using near-infrared (NIR) laser, PDT exacerbates tumor hypoxia, further promoting AZO-PRO activation. Our work introduces a novel approach to efficiently track and activate PROTAC prodrugs, enhance their antitumor efficacy, and mitigate off-target systemic toxicity.

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