Peptidylarginine deiminase 4 (PADI4), a new histone modification enzyme, which converts both arginine and monomethyl-arginine to citrulline, has gained massive attention in recent years as a potential regulator of gene transcription. Recent studies have shown that arginine residues R2, R8, R17, and R26 in the H3 tail and R3 in the H4 tail can be deiminated by PADI4. This kind of histone post-translational modification has the potential to antagonize histone methylation and coordinate with histone deacetylation to regulate gene transcription. PADI4 also deiminates non-histone proteins, such as p300, NPM1, ING4, RPS2, and DNMT3A. PADI4 has been shown to involve in cell apoptosis and differentiation. Moreover, PADI4 can interact with tumor suppressor p53 and regulate the transcriptional activity of p53. Dysregulation of PADI4 is implicated in a variety of diseases, including rheumatoid arthritis, tumor development, and multiple sclerosis. A wide variety of PADI4 inhibitors have been identified. Further understanding of PADI4 functions may lead to novel diagnostic and therapeutic approaches in these diseases. This review summarizes the recent progress in the study of the regulation mechanism of PADI4 on gene transcription and the major physiological functions of PADI4 in human diseases.

Osteosarcoma is the most common type of bone malignancy, and the pathogenesis has not been entirely elucidated yet. An important deimination modification enzyme PADI4 (peptidylarginine deiminase 4) has attracted much attention in recent years for its important function in several kinds of human tumors. However, the role of PADI4 on osteosarcoma tumorigenesis remains largely unrevealed. Here, we first assessed the effect of PADI4 on osteosarcoma proliferation by the CCK8 method and colony formation assay. Ectopically expressing PADI4 positively regulates the colony formation capacity of both U2OS and Saos‐2 cells. Furthermore, we explored the related mechanism and showed that PADI4 could stimulate Wnt/β‐catenin and MEK/ERK signaling in both U2OS and Saos‐2 cells. Then, we detected expression of PADI4 in human tissues of osteosarcoma and revealed that differential expression of PADI4 was associated with tumorigenesis of osteosarcoma. Last, we performed the in vivo experiment in nude mice and results also showed PADI4 could affect the tumor growth. In conclusion, this work revealed that PADI4 could upregulate the proliferation of osteosarcoma, mainly via the Wnt/β‐catenin and MEK/ERK signaling pathway. This study gives us new insight into the regulation mechanism of osteosarcoma proliferation and highlights PADI4 as a promising target for osteosarcoma diagnosis and treatment.

Osteoarthritis (OA) is a multifactorial degenerative joint disorder characterized by intricate interactions among oxidative stress, inflammation, apoptosis, and extracellular matrix (ECM) degradation, ultimately disrupting chondrocyte homeostasis and accelerating cartilage deterioration. Although advanced intra-articular biomaterial systems have improved local therapeutic delivery for OA, the rational integration of a multi-component bioactive core with a multifunctional carrier remains challenging. In this study, a multifunctional nanomedicine, K@BMT@HM, was developed by integrating a supramolecular bioactive core with a functionalized hydrogel microsphere carrier. The K@BMT core, composed of the KRFK peptide, bisdemethoxycurcumin (BDMC), and MnTBAP, exerted multi-dimensional regulatory effects by enhancing antioxidant defense, restoring autophagic flux, and modulating TGF-β-associated signaling, thereby mitigating oxidative stress, inflammation, and apoptosis while favoring ECM anabolic balance in chondrocyte-based assays. However, because TGF-β signaling is highly context- and compartment-dependent, these observations should not be interpreted as evidence that TGF-β activation is uniformly beneficial across the whole joint. Meanwhile, the HM-SCHW carrier, composed of chitosan (CS), sodium alginate (SA), hyaluronic acid (HA), and WYRGRL peptide, provided thermosensitive depot formation, lubrication, cartilage-associated localization/retention, and in vitro sustained/ROS-responsive release, thereby supporting localized delivery potential rather than proving WYRGRL-specific cartilage targeting. Moreover, the laser-responsive thermal behavior of K@BMT@HM provided a controllable local heating modality that may support thermosensitive in situ retention. Remarkably, the integrated K@BMT@HM, which couples the multi-component regulatory capacity of the K@BMT core with the multifunctional delivery advantages of the HM-SCHW carrier, was validated through a series of in vitro and in vivo experiments. Collectively, this work presents a rationally designed nanomedicine that integrates bioactive regulation with functionalized delivery to enhance chondroprotection, supporting further preclinical investigation of sustained and multimodal OA intervention. However, because the laser-assisted thermal component was validated only in a rat small-joint model, these findings cannot be directly extrapolated to human OA joints, where deeper articular cartilage and overlying skin, adipose tissue, synovium, and other tissues may substantially limit optical penetration and thermal delivery. In addition, because systematic single-component, two-component, and component-deletion controls were not performed, the present data should be interpreted as validating the integrated K@BMT@HM system as a whole rather than defining the quantitative contribution or indispensability of BDMC, MnTBAP, KRFK, 808-nm laser activation, the CS/SA hydrogel matrix, HA, or WYRGRL.