Rheumatoid arthritis (RA) is an autoimmune disease that is both chronic and systemic in nature. RA is influenced by hereditary, infection, autoimmune, and other impacts. The prevalence of RA ranges from 0.5 to 1%, with notable variations from the southern to the northern hemisphere and from urban to rural areas. The incidence of RA is lower in men than in women and increases trend with age. The primary symptoms of RA include joint pain, swelling, and stiffness [1]. The main therapeutic approach focuses on reducing inflammation, with the use of disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, as the primary clinical therapy for RA. However, long-term use of DMARDs may impact patients' immune function. Non-steroidal anti-inflammatory drugs (NSAIDs) can alleviate stiffness and pain and improve overall body function but do not slow down disease progression or interfere with joint damage. Glucocorticoids provide rapid symptom relief and disease improvement but lead to long-term side effects. Joint replacement surgery is often accompanied by pain and postoperative complications. Therefore, certain adjunctive treatments, such as probiotic bacteria and photobiomodulation (PBM), which have minimal side effects, are important in the treatment of RA [2,3]. Importantly, exploring the therapeutic mechanism can give us a deeper understanding of the advantages of LED in the treatment of RA, and also give us a new understanding of PBM, which has notable potential in photomedicine and photobiology applications.

The invasion of RA begins with autoimmunity, immune cells produce proinflammatory cytokines and stimulate synovial fibroblasts to transdifferentiate into pro-inflammatory and tissue damage subsets [4,5]. The pro-inflammatory subset exacerbates the autoimmune response, whereas the tissue destroying subset expresses receptor activator for nuclear factor-κB ligand (RANKL) and matrix metalloproteinases (MMPs) [6]. Under normal physiological conditions, synovial cells assume the role of lubricating and nourishing the surface of cartilage by secreting hyaluronic acid and joint lubricating fluid. During the onset of RA, the nourishing and lubricating function of synovial fibroblasts is also lost. Therefore, in the condition of inflammation of synovial fibroblasts differentiation makes it lost its original function and directly lead to the destruction of the bone [7,8].

As a member of the bone morphogenetic protein (BMP) family, BMP4 function is related to embryonic development, organogenesis, cell proliferation, and stem cell differentiation through the transforming growth factor-β (TGF-β) pathway [9]. BMP-2, −4, and − 7 stimulate bone formation and differentiation by binding to BMP receptor types I and II [10]. In the context of osteoarthritis (OA), in damaged OA cartilage chondrocytes, BMP-2 and BMP-4 mRNA and protein are found, while they are barely expressed in normal individuals. This suggests that BMP2 and BMP4 are involved in cartilage damage in OA patients [11]. In osteoblasts, BMP4 regulates osteoblast differentiation, which is vital of maintaining the dynamic equilibrium between osteoblasts and osteoclasts [3]. Additionally, a reduction in the expression of BMP4 protein has been noted in the synovial tissue of individuals diagnosed with RA [12].

Photobiomodulation (PBM) has emerged as a novel treatment method with characteristics such as low cost, low side effects, and convenient operation. It has been proven effective as an adjuvant treatment for RA [13]. Initially, PBM was used to be involved the cytotoxic reaction of photosensitive substances activated by light to achieve therapeutic effects. This mechanism involves direct light reaction with the cellular target or the reactive oxygen species production, such as singlet oxygen. Light emitting diode (LED) irradiation offers advantages such as a larger irradiation area, higher output power, lower cost, and enhanced safety [11,14]. Our previous studies have confirmed that red light irradiation at 630 nm using LED can prevent the migration and growth of MH7A cells and reduce the production of reactive oxygen species (ROS) in THP-1 cells, thereby decreasing inflammation [3,12]. Additionally, LED irradiation has been shown to attenuated inflammatory response and injury of joint in collagen-induced arthritis (CIA) mice by inhibiting NF-κB-mediated MMPs production [15]. These findings suggest that LED irradiation weaken the inflammatory response associated with RA. Notably, in this study, it was observed that BMP4 expression were changed in sequencing results after 630 nm LED irradiation. Experiments were performed to investigate the role of BMP4 in the treatment of 630 nm LED irradiation for RA. It not only enhances our understanding of the cellular responses to stimuli and light-induced factors, but also provides a new drug target for the treatment of RA.