Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics

Signal Transduction and Targeted Therapy REVIEW ARTICLE www.nature.com/sigtrans OPEN Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics Xiaofeng Dai1 ✉, Yuting Fan2,3 and Xing Zhao2 ✉ 1234567890();,: Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management. Signal Transduction and Targeted Therapy (2025)10:102 INTRODUCTION Systemic lupus erythematosus (SLE), canonically defined as an autoimmune disorder, can be considered as a chronic inflammatory illness with clinical manifestations encompassing various organs such as the blood vessels, brain, lungs, skin, kidneys and joints due to polymorphic biological alterations.1 It affects approximately 3.4 million people worldwide, with 400,000 individuals being newly diagnosed each year.2,3 It most commonly occurs among women between puberty and menopause,4 and individuals of the African origin have a higher risk of developing SLE.5–7 According to a 2023 global epidemiology study of SLE, Poland, the United States, Barbados, and China showed the highest SLE incidence.2 Though still with an unclear disease of origin, the chance of developing SLE is believed to be associated with genetic factors, epigenetic factors, environmental triggers, and hormonal factors.8 SLE can be diagnosed from the perspectives of disease onset and disease activity. These can be assessed using varied types of evaluation metrics such as the American College of Rheumatology (ACR) criteria and the SLE Disease Activity Index (SLEDAI). Besides, SLE is typically accompanied with increased risks of developing multiple types of comorbidities, with cancer screening being recommended by the European League Against Rheumatism (EULAR)9 and cerebrovascular disease being alarmed among female SLE patients by the American Heart Association.10 ; https://doi.org/10.1038/s41392-025-02168-0 SLE is caused by an autoimmune reaction involving both the innate and adaptive immune systems, where an abnormal immune response is directed to nucleic acid-containing cellular particles. The over production of antibodies targeting these nucleic acids, known as antinuclear antibodies (ANAs), is characteristic of SLE.8 Besides, the anti-Smith (anti-Sm) antibody, which is an auto-antibody directed against a component of the spliceosome, is highly specific to SLE, with 20-40% SLE patients versus approximately 1% healthy individuals carrying them.11 Various types of agents have been used for SLE therapeutics, ranging from cytokines, antibodies, hormones, inhibitors, antagonists, to the transfusion of fresh plasma and stem cells. Importantly, while several drugs initially designed for treating other pathological conditions have been shown effective in treating SLE such as the use of the anti-malaria agent hydroxychloroquine as a SLE therapeutic, a plethora of medications have been reported capable of inducing SLE. Examples of this kind include anti-arrhythmic agents such as procainamide, broadspectrum antibiotics such as minocycline, vasodilators such as hydralazine and methyldopa, and antipsychotics such as chlorpromazine. These have unanimously complicated our understandings on the appropriate therapeutics of SLE, rendering it necessary and urgent to delve into the molecular mechanisms driving SLE pathogenesis and classify current therapeutics accordingly by their mechanisms-of-action. This may guide 1 National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P. R. China; 2Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550004, P. R. China and 3Department of Gastroenterology, the Affiliated Hospital of Guizhou Medical University, Guiyang 550001, P. R. China Correspondence: Xiaofeng Dai () or Xing Zhao () These authors contributed equally: Xiaofeng Dai, Yuting Fan. Received: 4 September 2024 Revised: 26 November 2024 Accepted: 26 January 2025 © The Author(s) 2025 Systemic lupus erythematosus: updated insights on the pathogenesis,. . . Dai et al. 2 us towards effective management of SLE and, hopefully, help us identify the pivotal signaling axis for the establishment of innovative targeting strategies. Following the introduction of some basic knowledge of SLE including the history and epidemiology, this review characterized three key determinants of SLE pathogenesis by their mechanismsof-action, i.e., over-activated immune response, skewed cytokine microenvironment homeostasis, impaired debris clearance machinery; summarized current understandings on SLE diagnosis by disease onset, activity and comorbidity; introduced risk factors predisposing SLE at the genetic, epigenetic, hormonal and entrinsic levels; and classified current SLE preventive strategies and therapeutics by the identified working mechanisms. Our review not only provides comprehensive information on SLE so far available, but also proposes fresh insights on our current understandings of SLE, with a focus on its prevention and therapeutics. BASICS OF SLE Research history of SLE The history of SLE can be dated back to 400 Before Christ (BC) and divided into three perio (...truncated)