Wound healing is a dynamic and highly sequential process involving a series of overlapping spatial and temporal phases, including hemostasis, inflammation, proliferation, and tissue remodeling. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal, multidirectional differentiation potential, and paracrine regulation. Exosomes are subcellular vesicular components 30–150 nm in size and are novel carriers of intercellular communication in regulating the biological behaviors of skin cells. Compared to MSCs, MSC-derived exosomes (MSC-exos) possess lower immunogenicity, easy storage, and highly effective biological activity. MSC-exos, mainly derived from adipose-derived stem cells (ADSCs), bone marrow-derived MSCs (BMSCs), human umbilical cord MSCs (hUC-MSCs), and other stem cell types, play a role in shaping the activity of fibroblasts, keratinocytes, immune cells, and endothelial cells in diabetic wounds, inflammatory wound repair, and even wound-related keloid formation. Therefore, this study focuses on the specific roles and mechanisms of different MSC-exos in wound healing, as well as the current limitations and various perspectives. Deciphering the biological properties of MSC-exos is crucial to providing a promising cell-free therapeutic tool for wound healing and cutaneous regeneration. Graphical Abstract

As the most abundant and conserved internal modification in eukaryote RNAs, N6-methyladenosine (m⁶A) is involved in a wide range of physiological and pathological processes. The YT521-B homology (YTH) domain-containing family proteins (YTHDFs), including YTHDF1, YTHDF2, and YTHDF3, are a class of cytoplasmic m⁶A-binding proteins defined by the vertebrate YTH domain, and exert extensive functions in regulating RNA destiny. Distinct expression patterns of the YTHDF family in specific cell types or developmental stages result in prominent differences in multiple biological processes, such as embryonic development, stem cell fate, fat metabolism, neuromodulation, cardiovascular effect, infection, immunity, and tumorigenesis. The YTHDF family mediates tumor proliferation, metastasis, metabolism, drug resistance, and immunity, and possesses the potential of predictive and therapeutic biomarkers. Here, we mainly summary the structures, roles, and mechanisms of the YTHDF family in physiological and pathological processes, especially in multiple cancers, as well as their current limitations and future considerations. This will provide novel angles for deciphering m⁶A regulation in a biological system.

With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A poor understanding of the underlying biology has resulted in a lack of effective targeted therapeutic strategies. Tissue microarray and bioinformatics analyses have revealed that the downstream transcriptional coactivator of the Hippo pathway, transcriptional coactivator with PDZ-binding motif (TAZ), might be a therapeutic target in PDAC. Since pharmacological inhibition of TAZ is challenging, we performed unbiased deubiquitinase (DUB) library screening to explore the pivotal regulators of TAZ ubiquitination as potential targets in PDAC models. We found that USP14 contributed to Yes-associated protein (YAP)/TAZ transcriptional activity and stabilized TAZ but not YAP. Mechanistically, USP14 catalyzed the K48-linked deubiquitination of TAZ to promote TAZ stabilization. Moreover, TAZ facilitated the transcription of USP14 by binding to the TEA domain transcription factor (TEAD) 1/4 response element in the promoter of USP14. USP14 was found to modulate the expression of TAZ downstream target genes through a feedback mechanism and ultimately promoted cancer progression and liver metastasis in PDAC models in vitro and in vivo. In addition, depletion of USP14 led to proteasome-dependent degradation of TAZ and ultimately arrested PDAC tumour growth and liver metastasis. A strong positive correlation between USP14 and TAZ expression was also detected in PDAC patients. The small molecule inhibitor of USP14 catalytic activity, IU1, inhibited the development of PDAC in subcutaneous xenograft and liver metastasis models. Overall, our data strongly suggested that the self-amplifying USP14-TAZ loop was a previously unrecognized mechanism causing upregulated TAZ expression, and identified USP14 as a viable therapeutic target in PDAC.

Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), are critical effectors of the Hippo pathway, as well as other biochemical and biophysical signals. Through their interaction with DNA-binding partners, YAP/TAZ can modulate the transcription of many genes critical for organ size regulation and tissue homeostasis maintenance. Aberrant expression or activation of YAP/TAZ is implicated in the pathogenesis of many cancers and noncancerous diseases. Notably, their functional outputs demonstrate remarkable diversity, with context-dependent roles emerging across distinct disease models and tissue microenvironments. Posttranslational modifications (PTMs) exert profound impacts on the stability, subcellular localization, and function of YAP/TAZ. The canonical Hippo pathway-mediated phosphorylation and ubiquitination have been well characterized as mechanisms that downregulate YAP/TAZ stability and transcriptional activity. Recent studies have identified novel phosphorylation sites, atypical ubiquitination patterns, along with ubiquitin-like modifications, glycosylation, methylation, acetylation, and lactylation on YAP/TAZ. These PTMs exhibit dynamic regulation in response to microenvironmental stimuli, providing molecular insights into the context-dependent functional versatility of YAP/TAZ. This review systematically synthesizes current understanding of YAP/TAZ PTM networks and discusses their therapeutic implications.

Pyroptosis is a lytic and inflammatory form of gasdermin protein-mediated programmed cell death that is typically initiated by inflammasomes. The inflammasome response is an effective mechanism for eradicating germs and cancer cells in the event of cellular injury. The gasdermin family is responsible for initiating pyroptosis, a process in which holes are made in the cell membrane to allow inflammatory chemicals to escape. Mounting evidence indicates that pyroptosis is critical for controlling the development of cancer. In this review, we provide a general overview of pyroptosis, examine the relationship between the primary elements of pyroptosis and tumors, and stress the necessity of pyroptosis-targeted therapy in tumors. Furthermore, we explore its dual nature as a double-edged sword capable of both inhibiting and facilitating the growth of cancer, depending on the specific conditions. Ultimately, pyroptosis is a phenomenon that has both positive and negative effects on tumors. Using this dual impact in a reasonable manner may facilitate investigation into the initiation and progression of tumors and offer insights for the development of novel treatments centered on pyroptosis.

Malignant melanoma represents a particularly aggressive type of skin cancer, originating from the pathological transformation of melanocytes. While conventional interventions such as surgical resection, chemotherapy, and radiation therapy are available, their non-specificity and collateral damage to normal cells has shifted the focus towards immunotherapy as a notable approach. Extracellular vesicles (EVs) are naturally occurring transporters, and are capable of delivering tumor-specific antigens and directly engaging in the immune response. Multiple types of EVs have emerged as promising platforms for melanoma vaccination. The effectiveness of EV-based melanoma vaccines manifests their ability to potentiate the immune response, particularly by activating dendritic cells (DCs) and CD8+ T lymphocytes, through engineering a synergy of antigen presentation and targeted delivery. Here, this review mainly focuses on the construction strategies for EV vaccines from various sources, their effects, and immunological mechanisms in treating melanoma, as well as the shortcomings and future perspectives in this field. These findings will provide novel insights into the innovative exploitation of EV-based vaccines for melanoma immune therapy.