Acta Pharmaceutica Sinica B

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Ferroptosis meets cancer immunotherapy: Overcoming the crosstalk challenges through advanced drug delivery strategies

Acta Pharmaceutica Sinica B. 2025, 15(12): 6307-6341.

The integration of ferroptosis induction with cancer immunotherapy has emerged as a promising approach in oncology, offering dual mechanisms to overcome therapeutic resistance and tumor heterogeneity. Nevertheless, the dynamic and complicated crosstalk between ferroptosis processes and immune regulation in tumor microenvironments presents both opportunities and challenges. By inducing lipid peroxidation in tumor tissues, ferroptotic tumor cell death can stimulate immunogenicity. Nevertheless, excessive lipid peroxidation may paradoxically impair the functionality of multiple immune cells, thereby presenting crosstalk challenges in therapeutic strategies. To address these crosstalk challenges, several advanced drug delivery strategies have been proposed, such as immunostimulatory active pharmaceutical ingredients co-delivery, tumor-targeted delivery, and stimuli-responsive delivery. These drug delivery strategies demonstrate dual therapeutic efficacy by synergistically potentiating ferroptosis induction in malignant cells while concurrently mitigating immunotoxicity and even augmenting antitumor immunity. This review offers detailed insights into the crosstalk between ferroptosis and tumor immunity, along with a guiding overview of the three delivery strategies. The current obstacles and translational potential were thoroughly analyzed, providing valuable perspectives for future research.
Author correction to “AI-integrated IQPD framework of quality prediction and diagnostics in small-sample multi-unit pharmaceutical manufacturing: advancing from experience-driven to data-driven manufacturing” [Acta Pharm Sin B 15 (2025) 4193-4209]

Acta Pharmaceutica Sinica B. 2025, 15(12): 6743-6744.
Decoding helical dynamics in viral replication: Cryo-EM unveils conserved assembly mechanisms and broad-spectrum antiviral targets

Acta Pharmaceutica Sinica B. 2025, 15(12): 6735-6738.
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.
Hemoglobin nanocatalyst with tunable autoxidation activity for tumor apoptosis-ferroptosis combination therapy

Acta Pharmaceutica Sinica B. 2025, 15(12): 6626-6637.

The clinical translation of catalytic therapy has been hindered in recent decades due to immunological risks, delayed degradation, and poorly understood metabolism associated with catalysts, despite promising results in antitumor therapy. Developing catalysts with nonmetallic active centers may provide an alternative to those with metallic active centers. In this study, a natural protein nanocatalyst, Hb@PtPP, is developed through the moderate polymerization of pyrrole and hemoglobin for tumor catalytic therapy. In comparison with BSA@PtPP prepared from bovine serum albumin, Hb@PtPP exhibits distinctive autoxidation activity in tumor cells in response to elevated hydrogen peroxide levels while maintaining relatively low activity in normal cells. This feature enables Hb@PtPP to effectively combat tumors by initiating a cascade of catalytic reactions, including the production of reactive oxygen species, the release of heme and iron ions, and the accumulation of lipid peroxidation, all of which contribute to apoptosis and ferroptosis in tumor cells. RNA-sequencing results further demonstrate that tumor cells undergo ferroptosis. Additionally, these catalytic processes are augmented by the photothermal effect, resulting in efficient tumor killing and growth inhibition both in vitro and in vivo. This study underscores the crucial role of hemoglobin in advancing catalytic therapy for tumors.
Graph neural networks driven acceleration in drug discovery

Acta Pharmaceutica Sinica B. 2025, 15(12): 6163-6177.

Graph neural networks (GNNs) are revolutionizing drug design processes. Over the past five years, GNNs have emerged as transformative tools by accurately modeling molecular structures and interactions with binding targets. Breakthroughs in predicting molecular properties, drug repurposing, toxicity assessment, and interaction analysis, along with generative GNNs enhancing virtual screening and novel molecule design, have significantly sped up drug discovery. These GNN-driven innovations improve predictive accuracy, cut development costs, and reduce late-stage failures. This review focuses on the interdisciplinary integration of GNNs throughout the discovery process, including lead discovery and optimization, synthetic route design, drug–target interaction prediction, and molecular property profiling, while critically evaluating the challenges in translational medicine.
Probiotic living microneedles designed by interbacterial competition for accelerated infected wound healing

Acta Pharmaceutica Sinica B. 2025, 15(12): 6571-6586.

Probiotic therapy offers a promising strategy for chronic infected wound management through pathogen suppression and immune modulation. However, its efficacy remains restricted by weak competitiveness in pathogen-rich niches and poor penetration across biofilm barriers. Inspired by bacterial competitive interactions, we developed a multifunctional microneedle (MN) platform to overcome these limitations. Lactobacillus reuteri (Lr) was coated with poly-l-lysine-modified metal–phenolic networks (MPNs) encapsulating doxorubicin (DOX), yielding DOX@MPN–PLL@Lr (DMP@Lr). The engineered probiotics were incorporated into dissolving MNs enriched with nutrient broth to ensure excellent microneedle performance and probiotic function. This design leverages MPN multifunctionality to reduce early-stage pathogenic burden via photothermal-assisted bacterial killing and near-infrared (NIR)-promoted antibiotic release, thereby enhancing probiotic competitiveness. Meanwhile, MNs physically disrupt biofilms for precise delivery into deep infection sites. In vitro, DMP@Lr achieved >99.9% (5.5 log) bactericidal efficiency, and its MNs exhibited a 1.4-fold higher biofilm clearance compared with blank MNs. In vivo, a single DMP@Lr MN patch promoted 93.9% wound closure, demonstrating potent antibacterial activity and accelerated healing. This study presents an innovative, translatable probiotic-based MN therapy for the effective treatment of chronically infected wounds.
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.
m⁶A readers: Promising therapeutic targets in cancer treatment

Acta Pharmaceutica Sinica B. 2025, 15(12): 6178-6198.

N⁶-methyladenosine (m⁶A) represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation, significantly impacting gene expression through the selective recognition by m⁶A reader proteins. Aberrant expression of m⁶A readers has been associated with cancer progression, contributing to tumor growth, metastasis, drug resistance, and immune evasion. With the increasing research on m⁶A readers, the discovery of small-molecule inhibitors targeting these proteins has emerged as a promising avenue for cancer therapy. This review delineates the classification and functional roles of m⁶A readers across various cancers. Furthermore, we summarize and discuss the recent progress in the development of small-molecule inhibitors, with a focus on the medicinal chemistry perspectives. We hope to provide valuable insights to guide future efforts in drug discovery and rational design targeting m⁶A readers for innovative cancer therapeutics.
Butyrylated Smilax glabra starch relieves atopic dermatitis through gut-skin axis modulation via colon-targeted delivery

Acta Pharmaceutica Sinica B. 2025, 15(12): 6587-6606.

Atopic dermatitis (AD) is a prevalent cutaneous condition with chronic inflammation and immune dysregulation, posing a public health concern owing to its long-lasting and recurrent nature. Butyrate, a short-chain fatty acid produced by gut microbiota, exhibits significant anti-inflammatory effects in AD. Yet, its delivery via butyrylated starch for prolonged release in the colon has not been adequately investigated. In this study, butyrylated Smilax glabra starch (BSGS) was synthesized and its therapeutic potential against AD via modulation of the gut–skin axis was examined. BSGS exhibited a C-type crystalline structure and highly resistance to gastrointestinal digestion. In vitro anaerobic fermentation showed that BSGS effectively promoted the generation of short-chain fatty acids, especially butyrate, and positively influenced the gut microbial composition. In AD mice, BSGS administration considerably mitigated cutaneous inflammation, lowered serum proinflammatory cytokines, restored intestinal barrier integrity, and modulated gut microbiota by increasing Bacteroides and norank_f__Prevotellaceae while decreasing Alistipes and norank_o__RF39. This therapeutic effect was associated with butyrate release and NF-κB pathway suppression, as evidenced by the reduced phosphorylation of p65 and IκBα. These findings establish that BSGS, a novel colon-targeted butyrate donor, holds promising potential in AD treatment by modulating the immune system via the gut–skin axis.

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