Acta Pharmaceutica Sinica B

Unveiling the bioactive landscape of drug inactive ingredients (DIGs) using deep transfer learning

Acta Pharmaceutica Sinica B. 2026, 16(7): 4128-4146.

In a drug product, the major components by mass are the drug inactive ingredients (DIGs), which raises great concerns about their unwanted effects and clinical toxicities. It is demanded to unveil their proteome-wide bioactive landscape using computational methods. However, existing methods are impeded by either incapability to scan human proteome or inaccuracy in DIGs’ bioactivity prediction. Here, a cross-attention transformer model, titled TransDIG, leveraging cross-module deep transfer learning was therefore developed to map the bioactive landscape of DIGs using minimal experimental data. First, the generalizability and interpretability of this model was verified by the prediction of zero-shot proteins and identification of key atoms/residues, respectively. Then, the bioactive landscape of hundreds of DIGs was unveiled using TransDIG, and thousands of potential bioactivities were found for the DIGs currently employed in pharmaceutical industry. Finally, the bioactivities of four popular DIGs were identified based on the landscape and experimentally validated by activity assay. As a result, the colorant β-carotene was validated to inhibit a critical drug transporter, and our study presented the first in vitro evidence of the bioactivity of the antioxidant dodecyl gallate that has not previously been reported to regulate any human protein. This study might offer insights for the design of drug formulation and its clinical utilization.

Revolutionizing drug discovery from natural products: The roles of artificial intelligence and multi-omics in accelerating innovation

Boyang Wang, Qingyuan Liu, Weibo Zhao, Tingyu Zhang, Dingfan Zhang, Chayanis Sutcharitchan, Shao Li

Acta Pharmaceutica Sinica B. 2026, 16(7): 4103-4127.

Natural products and their derivatives have long been crucial in drug therapy, especially in traditional medicine. However, challenges in screening, isolation, characterization, and optimization have slowed their development in the pharmaceutical industry. Recent advancements in artificial intelligence (AI) and multi-omics technologies are revitalizing this field. AI offers powerful tools for understanding natural compounds, enhancing molecular representations, and supporting tasks such as binding prediction, drug repurposing, and retrosynthesis. Moreover, generative models are aiding in natural product optimization and the creation of pseudo-natural compounds. At the same time, multi-omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have enabled high-throughput studies of plant traits, synthesis, regulatory mechanisms, and quality control, providing valuable data for AI model development. These advancements help accelerate the discovery of new compounds with medicinal potential. Furthermore, in the field of traditional Chinese medicine research, which is largely based on natural plant sources, AI systems exemplified by UNIQ system, combining AI and multi-omics, have been instrumental in mechanistic studies and new drug development. This study comprehensively discusses the algorithms and applications of AI and multi-omics technologies in the drug development of natural compounds and plants, as well as summarizing relevant databases which might provide high-quality data for the future development of AI algorithms targeting natural products.

Editorial of special column on machine learning in drug discovery

Guobo Li, Changguo Zhan

Acta Pharmaceutica Sinica B. 2026, 16(7): 3994-3995.

Steroid hormone ouabain cooperates with Na⁺,K⁺-ATPase to improve innate immunity against bacterial infections through a non-classic training mechanism regulated by mRNA reprogramming

Lili Chen, Kuida Chen, RunRun Shan, Jinjun Bian, PeiPei Jin, Hao Lin, Jian Liu, Yan Chen, Siyao Zhu, Fangzhou Yin, Wu Yin

Acta Pharmaceutica Sinica B. 2026, 16(6): 3655-3679.

Epigenetic reprogramming underpins trained immunity (TRIM). However, the importance of mRNA reprogramming in TRIM remains unknown. Here, we discovered, for the first time, that the steroid hormone ouabain creates a significant training effect on peripheral innate immune cells (IICs), leading to functional enhancement of IICs against bacterial infections. However, unlike conventional training mechanisms, ouabain primarily relies on an integrated posttranscriptional RNA regulon complex (IPRRC) to establish immune memory and reprogram cytokine expression, with lncRNA-CYTOR playing a critical role in this process. Moreover, to enhance training effects while reducing lactate production, ouabain promotes a rapid degradation of the Na⁺,K⁺-ATPase receptor. Pathologically, endogenous ouabain is downregulated in sepsis-induced immunoparalysis in vivo, correlating with impaired innate immunity. Exogenous ouabain rescue significantly reverses this impairment, and its effect is superior to β-glucan, even when used at one percent of β-glucan dosage. Notably, posttranscriptional RNA regulons are also critically involved in β-glucan’s training effects. Overall, mRNA reprogramming emerges as a new mechanism for TRIM; steroid hormone ouabain is a novel innate immunity regulator.

Ginsenoside Rg1 alleviates post-ischemic stroke neuroinflammation by inhibiting CKLF1-mediated suppression of dead/dying neuron clearance

Acta Pharmaceutica Sinica B. 2026, 16(6): 3632-3654.

The reduction of dead/dying neurons represents a critical mechanism for the anti-acute ischemic stroke (AIS) effect of Panax notoginseng, however, its molecular basis remains unclear. Recent findings implicate chemokine-like factor 1 (CKLF1) as a key contributor to the impaired clearance of dying neurons. Here, we established an integrated high-throughput screening strategy combining biolayer interferometry (BLI), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and NanoBRET technologies to identify CKLF1 inhibitors among Panax notoginseng saponins (PNS). Of note, ginsenoside Rg1 (GRg1) exhibits the highest affinity for CKLF1 and the most potent inhibitory efficacy against the CKLF1-CCR4 interaction, effectively suppressing CKLF1-C27 peptide-induced calcium influx and cytokine production. In experimental AIS models, GRg1 confers neuroprotective properties by mitigating ischemic brain damage and promoting neuronal functional recovery. Mechanistically, GRg1 binds to CKLF1 and modulates the mTORC1/TFEB pathway, enhancing lysosomal function and thereby facilitating the clearance of dead/dying neurons. This study presents an efficient approach for the discovery of natural CKLF1 inhibitors and highlights GRg1 as a promising therapeutic candidate for enhancing the clearance of dead/dying neurons in AIS.

Potential oncogenic risks of Keap1-targeting PROTACs: Caution warranted in drug design

Zhe Zhao, Wen Ma, Jincen Hao, Gaofei Hu, Xinfeng Wang

Acta Pharmaceutica Sinica B. 2026, 16(6): 3985-3987.

Discovery and mutasynthetic optimization of ansatrienin B: A new broad-spectrum inhibitor against RNA viruses

Acta Pharmaceutica Sinica B. 2026, 16(6): 3963-3984.

RNA viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses, and alphaviruses, represent a major source of emerging human infectious diseases. They pose a persistent threat to public health; however, few therapeutic options are available for severe infections. Through a natural product screening campaign, we identified ansatrienin B as a broad-spectrum inhibitor of multiple RNA viruses, including SARS-CoV-2, flaviviruses (e.g., YFV, WNV, DENV), and alphaviruses (e.g., CHIKV). Time-of-drug-addition assays indicated that ansatrienin B acts at both the early (entry) and intermediate (replication) stages of the viral life cycle. Surface plasmon resonance (SPR) and molecular docking studies validated a direct interaction between ansatrienin B and the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and WNV. Combined RNA pull-down and RdRp enzymatic activity assays (in gel, solution, and cellular forms) further demonstrated that ansatrienin B disrupts both the binding of RdRp to viral RNA and its enzymatic activity. In vivo, ansatrienin B showed significant efficacy in mouse models infected with SARS-CoV-2 or WNV infection. To facilitate screening and elucidate the structure-activity relationship (SAR), we generated a focused ansatrienin library via a mutasynthetic approach. Supplementation of four 3,5-AHBA analogs into a △mycB1-B4 mutant strain of Streptomyces flaveolus yielded 30 novel ansatrienin derivatives. Evaluation of anti-SARS-CoV-2 activity identified four analogs with enhanced potency, enabling the establishment of a preliminary SAR. Collectively, these findings establish ansatrienin B as a novel inhibitor targeting RdRp and provide a foundation for the development alternative broad-spectrum antiviral agents.

Two receptors, one molecule: Reprogramming bile acid signaling for cardioprotection

Acta Pharmaceutica Sinica B. 2026, 16(6): 3990-3991.

Interleukin 12-tethered nano-aluminum adjuvant orchestrates environmental immunomodulation to empower cytotoxic T cells against solid tumors

Acta Pharmaceutica Sinica B. 2026, 16(6): 3892-3906.

The immunosuppressive tumor microenvironment (TME) profoundly limits the therapeutic efficacy of CD8⁺ T cells in solid tumors. While cytokine therapies have shown promise in reactivating CD8⁺ T cells, they fail to address the common suppressive environmental attributes (e.g., acidosis and Mg²⁺ deficiency) of solid tumors. Here, we report an innovative CD8⁺ T cell dual-functional modulator, interleukin-12-tethered nano-aluminum adjuvant (IL12@NAM), which counteracts the acidic TME to relieve acidosis and concurrently releases Mg²⁺ and IL12. Locally released Mg²⁺ and IL12 synergize in T cell infiltration and activation by promoting the phosphorylation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, and enhance CD8⁺ T cell activation and functions via the Ca²⁺-nuclear factor of activated T cells 2 pathway. Furthermore, dual-functional IL12@NAM mitigates CD8⁺ T cell exhaustion by reducing PD1 and LAG3 expression and effectively increases the differentiation towards T helper 1 cells while decreasing regulatory T cells, creating a more favorable immune network for enhanced CD8⁺ T cell-mediated anti-tumor immunity. As a result, IL12@NAM has demonstrated potent therapeutic efficacy against advanced melanoma and breast cancer, and remarkably empowered adoptive T therapy of solid tumors. This study provides a paradigm for empowering cytotoxic T cells by reactivating and creating a sustainable immunoresponsive environment, offering a potential adjuvant strategy to enhance solid tumor therapy.

Structural insights into pterocarpan reductases unveil a universal ring-opening mechanism in plant biosynthesis of 4-(furan-2-yl) phenol derivatives

Acta Pharmaceutica Sinica B. 2026, 16(6): 3953-3962.

Pterocarpans and isoflavans are important phytoalexins, and demonstrate significant benefits to human health. Pterocarpan reductases (PTRs) catalyze the conversion of pterocarpans to isoflavans, while the catalytic mechanism remains unknown. Herein, we report six PTRs (GuPTR1-6) from Glycyrrhiza uralensis, together with the first PTR crystal structure (GuPTR1/(-)-medicarpin/NADP⁺, 1.8 Å). Structural analysis and mutagenesis reveal that a lysine-mediated deprotonation of the 7-OH group triggers C‒O bond cleavage of pterocarpans in the furan ring-opening reactions. This mechanism also applies to similar ring-opening enzymatic reactions. Through ancestral sequence reconstruction, we obtained a multifunctional reductase N0, which could accept different types of 4-(furan-2-yl) phenol derivatives as substrates. This study not only unveils the catalytic mechanisms of PTRs, but also provides a powerful enzymatic tool for the synthesis of bioactive isoflavans.