Xiaoyan Shen

Skin aging represents a multifaceted degenerative process that predisposes to dermatological pathologies, including infections, dermatitis, and malignancies, causing great physical and psychological distress to patients. Conventional therapies, including topical antioxidants and sunscreens, have shown limited efficacy with safety concerns that continue to pose a substantial challenge in the treatment of skin aging. In this context, we pioneered the therapeutic application of Gynostemma pentaphyllum-derived extracellular vesicles (GPEVs), demonstrating their unprecedented efficacy in alleviating UVB-induced skin aging. Specifically, GPEVs restored epidermal integrity by inhibiting collagen degradation and DNA damage, while improving skin hydration. In vitro, the administration of GPEVs led to reduced SA-β-gal activity, enhanced cell proliferation, and diminished senescence-associated secretory phenotype (SASP). Mechanistically, GPEVs prevented CTCF-mediated transcriptional activation of aging-related genes via promoting targeted STING degradation. Notably, the therapeutic effects of GPEVs were entirely abolished upon STING agonism, thereby confirming the target specificity. Our study not only establishes GPEVs as a biocompatible nanotherapeutic agent for addressing skin aging but also represents a paradigm-shifting strategy for the utilization of plant-derived extracellular vesicles, bridging critical gaps in current anti-aging dermatology.

PF-3758309, a pyrrolopyrimidine-based inhibitor of p21-activated kinase 4 (PAK4), has demonstrated preclinical anti-tumor activity. However, due to poor pharmacokinetics and off-target effects, it has not advanced to clinical use. In this study, we conducted a comprehensive multi-omics analysis, including proteomics, transcriptomics, and ubiquitinomics, to investigate the mechanism of PF-3758309 in HCT116 cells. Our results revealed that PF-3758309 promotes the degradation of RNA polymerase II subunit proteins (POLR2A/B/E) via the cullin-RING ligase pathway. This process is mediated by the E3 ubiquitin ligase DNA damage-binding protein 2 (DDB2), and is independent of PAK4. Furthermore, the small-molecule inhibitor MLN4924, which blocks NEDD8-activating enzyme, reversed the degradation of POLR2A/B/E, supporting the role of ubiquitin-proteasome pathways in this process. Functional assays confirmed that PF-3758309 inhibits tumor cell growth and migration by promoting ubiquitination-dependent degradation of POLR2A/B/E. These findings uncover a previously unrecognized mechanism of PF-3758309’s anti-tumor activity and provide a basis for further investigation into its therapeutic potential.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by a progressive breakdown of immune tolerance to self-antigens, resulting in multiple tissue damage and clinical symptoms. Innate and adaptive immune cells including dendritic cells, macrophages, myeloid-derived suppressor cells (MDSCs), T cells and B cells are the key drivers in perpetuating and amplifying of this systemic disease. In this review we offer a comprehensive overview of recent advances in understanding the immune-pathogenesis of SLE with particular emphasis on regulatory immune cells exhibiting immunosuppressive properties, as well as newly identified factors influencing immune cell function and lineage differentiation. Furthermore, we discuss traditional Chinese medicine and natural extracts that have shown therapeutic effects on SLE by modulating immune cell differentiation and function, which may provide insights into their clinical applications.