A preclinical study has developed a precision nano-intervention strategy targeting tumor-associated nerves to destroy nerve-fueled tumor growth in pancreatic cancer. In this strategy, Escherichia coli Nissle 1917-derived outer membrane vesicles (OMVs) are decorated with nerve-binding peptide for targeted delivery of co-loaded tropomyosin receptor kinase (Trk) inhibitors to tumor-associated nerves, thus precisely inhibiting nerve activity through the neurotrophin/Trk signaling pathway. Furthermore, the OMVs trigger M2-M1 switching, thus accelerating nerve injury. This nano-intervention strategy significantly enhances chemotherapy efficacy in pancreatic cancer.

Aging impairs adipose tissue function and contributes to metabolic disorders, such as obesity and insulin resistance. Chronic inflammation is mediated by cytokines, including IL-6, IL-1β, and TNF-α, is a pivotal factor in aging that links mitochondrial dysfunction to activation of the NLRP3 inflammasome in aged adipose tissue. Moreover, distinct adipose tissue and adipose tissue depots exhibit complex molecular and cellular functions related to the deterioration of conventional metabolic regulation pathways. Unraveling these mechanisms is crucial for developing therapeutic strategies to enhance metabolic health and promote longevity. This review elucidates the current understanding of lipid metabolism, insulin resistance, cellular senescence, and mitochondrial dysfunction. Moreover, strategies to improve mitochondrial quality control in aging adipose tissue, such as mitochondrial transplantation, hold promise for addressing mitochondrial dysfunction. Finally, a novel therapeutic approach for mitochondrial transplantation is proposed using exosome cargo to sustain healthy metabolism and thermogenesis in aging populations. These findings lay the groundwork for innovative therapies and preventive strategies to mitigate the impact of obesity and aging.

The HIV-1 capsid protein (CA) plays a crucial role in viral replication by orchestrating nuclear entry through interactions with host nuclear pore complexes (NPCs). Recent research has revealed that HIV-1 CA actively disrupts NPC architecture via phenylalanine-glycine (FG)-repeat nucleoporin interactions, thereby enabling nuclear translocation of viral components. This mechanistic insight has driven the development of lenacapavir, the first-in-class CA inhibitor approved for multidrug-resistant HIV-1. Lenacapavir competitively blocks CA-NPC binding, stabilizes cytoplasmic capsids, disrupts viral maturation, and demonstrates pan-stage antiviral efficacy and long-acting pharmacokinetics. Clinical trials have indicated its 100% prophylactic efficacy and potential to decrease global HIV incidence. Advances in structural biology, molecular dynamics simulations, and nanotechnology are expected to further inform next-generation therapeutic strategies targeting CA-host interactions. These findings not only redefine HIV-1 treatment paradigms but also have broader implications for combating CA-dependent viruses.

Psoriasis is a chronic inflammatory disorder for which phosphodiesterase-4 (PDE4) inhibitors have emerged as promising therapeutic agents due to an ability to regulate inflammatory signaling pathways. In this study 1200 methanolic extracts from Chinese medicinal plants were screened and Eclipta prostrata (L.) Linn. ( E. prostrata) was shown to have potent PDE4 inhibitory activity. Bioassay-guided fractionation further demonstrated that the ethyl acetate (EA) fraction exhibited the highest inhibitory activity, leading to the isolation of wedelolactone (WDL) as the principal bioactive compound (IC₅₀ = 2.8 μM). Molecular dynamics simulations revealed that WDL forms stable interactions with PDE4D through hydrogen bonding and hydrophobic contacts. E. prostrata-EA and WDL significantly suppressed pro-inflammatory cytokines in keratinocytes in vitro. Topical application of WDL demonstrated superior anti-psoriatic efficacy compared to calcipotriol in vivo, as evidenced by reduced Psoriasis Area and Severity Index scores, normalized epidermal thickness, and improved inflammatory cytokine profiles. WDL exhibited favorable metabolic stability in liver microsomes and demonstrated a good safety profile in subacute toxicity assessments with no systemic toxicity. These findings established WDL as a potent and safe topical PDE4 inhibitor, highlighting the potential of WDL as a novel therapeutic candidate for psoriasis and warranting further clinical development.

Tumor ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for combating cancers, particularly in cases involving cancer stem cells (CSCs) and drug resistance. In recent years nanomaterial-based approaches have gained significant attention for the potential to selectively induce ferroptosis in cancer cells while sparing normal tissues. This review aims to provide a comprehensive overview of the current state-of-the-art in utilizing nanomaterials for targeting tumor ferroptosis with a specific focus on the application in eradicating CSCs and overcoming drug resistance mechanisms. The molecular mechanisms underlying ferroptosis induction by nanomaterials, the unique properties and functionalities of various nanomaterial platforms, and strategies for targeting CSCs and overcoming drug resistance using nanoferroptosis approaches will be discussed. In addition, the preclinical and clinical evidence supporting the efficacy of nanomaterial platforms will be evaluated. Furthermore, the challenges and future perspectives in the development and translation of nanoferroptosis-based therapies for precision cancer treatment will be highlighted.

Proteolysis targeting chimera (PROTAC) technology has emerged as a powerful tool in drug discovery that enables targeted protein degradation through a unique bifunctional approach. This review provides a comprehensive overview of PROTACs with a focus on recent advances in enhancing selectivity and therapeutic potential. We begin with an in-depth discussion of the structure and mechanism of PROTACs, comparing PROTACs to traditional small molecule inhibitors and exploring how PROTACs overcome limitations, such as drug resistance and targeting previously undruggable proteins. Key to this discussion is the concept of selectivity in PROTAC design, including optimization of E3 ligases and linker structures to improve target engagement and minimize off-target effects. The review also highlights the potential of covalent PROTACs in enhancing specificity and efficacy. Furthermore, various target classes for PROTAC development are explored, including epigenetic regulators (e.g., BET proteins and histone deacetylases), cell cycle and signaling pathway proteins (e.g., CDKs, BCL-XL, and p38 MAPK), receptor and kinase targets (e.g., EGFR and BRAF), and immune regulators (e.g., CREBBP and IRAK3). We discuss the implications of targeting these proteins for cancer and other diseases, emphasizing the promise of PROTACs in transforming therapeutic strategies. Finally, the review highlights ongoing challenges, such as optimizing pharmacokinetics and clinical validation, and provides future perspectives on the evolution of PROTAC technology.

Neurologic disorders are the leading cause of illness and disability as a result of increased life expectancy and global population aging, highlighting the urgent need and great challenge for discovering neuroprotective agents with better efficacy and minimal side-effects. Catalpol, an iridoid glycoside derived from Rehmanniae Radix, has therapeutic potential in neurologic diseases due to its diverse biological activities. This review summarizes the research advances and therapeutic potential of catalpol for a wide range of neurologic disorders, including depression, cognitive impairment, stroke, Parkinson’s disease, and multiple sclerosis. A comprehensive discussion of experimental models used, dosages, duration of treatment, and mechanisms involved is provided. The common mechanisms underlying the neuroprotective effects of catalpol on these neurologic disorders are closely related to antioxidant, anti-neuroinflammatory, and anti-apoptotic properties, as well as the capacity to promote neuroplasticity and neurogenesis. Despite the promising results from experimental studies, there are still challenges to be addressed, such as identifying direct binding targets, assessing toxicologic effects, and understanding pharmacokinetics. Furthermore, well-designed and controlled clinical trials should be conducted to validate the efficacy and safety for treating various neurologic conditions. This review provides compelling evidence supporting catalpol as a promising natural neuroprotective agent.

In addition to regulating lipid biosynthesis and uptake, sterol regulatory element binding protein (SREBP) is involved in mediating biological signaling networks. SREBP is a key transcription factor in the regulation of physiologic and pathologic lipid metabolism processes. “SREBP” was used as a keyword in searches on the Web of Science, Elsevier, Science Direct, and CNKI databases for relevant literature from 2021 to October 2024; the search results were analyzed. SREBP is first synthesized as an inactive precursor, then cleaved to release active NH₂-terminal domains. Mature SREBP enters the nucleus and promotes transcription of downstream genes by binding to the promoter elements of target genes. The classical pathway of SREBP precursor activation refers to transporter cleavage that is dependent on SCAP in response to signals from intracellular sterol depletion. However, in the case of endoplasmic reticulum stress, SREBP is activated via caspase-2 and independent of feedback inhibition by steroids or excess lipid uptake. Furthermore, the mechanism of action underlying SREBP in different diseases, as well as synthetic and natural compounds that inhibit SREBP activity, are summarized to provide new insights into SREBP as a therapeutic target for diseases.

The prevalence of diabetes is increasing and expected to become a major global health burden. Various pharmaceutical approaches have been used to manage diabetes and reduce the associated risks. Subcutaneous insulin injection remains the primary treatment due to the physicochemical properties of insulin, which limit oral absorption. The gastrointestinal tract presents further challenges, including enzymatic degradation and harsh environmental conditions, resulting in oral insulin bioavailability < 1%. As a result, alternative delivery routes, such as transdermal delivery, have been extensively explored. However, this approach is also challenging due to the structural barriers of the skin, which hinder drug absorption. The high molecular weight of insulin further limits permeation across the skin. To address these limitations, various formulation and delivery strategies have been investigated to improve transdermal drug delivery of insulin and are the subject of this review. Approaches, including penetration enhancers, lipid-based carriers, microemulsion, polymeric systems, and physical enhancement technologies, have demonstrated potential for enhancing skin permeability. However, the potential adverse effects and patient discomfort associated with these conventional methods highlights the need for more user-friendly alternatives. Microneedles have emerged as a promising transdermal delivery system, offering a painless, simple, and user-friendly approach to overcome challenges, thus improving adherence and treatment efficacy.

Geroprotectors that delay aging have substantial potential for preventing and mitigating age-related diseases. Natural products derived from traditional herbal medicines are promising candidates for geroprotector discovery, because of their multi-target mechanisms and preventive health benefits. Through screening of 836 Chinese herbal medicine extracts, we identified that the leaf extract of Caryota maxima ( JM13001) significantly extended lifespan and healthspan in Caenorhabditis elegans. JM13001 increased total lipid content and upregulated mono-unsaturated fatty acids (MUFAs), which are known to contribute to longevity. JM13001 exerted its effects through DAF-2 signaling, thereby promoting lipid accumulation and extending lifespan in nematodes. Notably, the lifespan-extending effects of JM13001 were abolished after the loss of key enzymes responsible for converting saturated fatty acids to MUFAs or after oleic acid supplementation; therefore, its geroprotective effects are dependent on MUFAs. Chemical analysis revealed that JM13001 contains flavonoids such as rutin, isoquercitrin, and kaempferol-3-O-rutinoside, among which rutin alone was sufficient to reproduce the anti-aging and lipid accumulation promotion effects of JM13001 through DAF-2 signaling. This study identifies a novel geroprotective herbal extract and its active ingredient, thereby providing insights into the anti-aging mechanisms of natural geroprotectors via MUFA metabolism regulation.