Vitiligo is mainly characterized by distinct white patches on the skin. The condition involves many factors and has a complex etiology, such as autoimmune responses, genetic predispositions, and oxidative stress [1], [2], [3]. Recent studies have shown that an autoimmune attack occurs on basal epidermal melanocytes, classifying vitiligo as an immune-mediated pigmentation disorder [4]. Epidemiological studies have found that vitiligo increases the risk of several autoimmune diseases, such as alopecia areata, type 1 diabetes, psoriasis, pernicious anemia, autoimmune hypothyroidism, autoimmune Addison's disease, and rheumatoid arthritis. Although vitiligo only affects patients' appearance, these co-morbidities can seriously affect the health [5]. Therefore, further studies that assess the role of vitiligo in the development of these diseases and their pathogenesis are necessitated. However, most previous studies were observational, and the findings might be affected by confounding factors and reverse causality. Furthermore, the role of vitiligo in the development of autoimmune diseases is still unclear.

Vitiligo, as a chronic dermatological condition affecting skin, remains largely obscure in terms of its pathophysiological mechanisms. Advances in metabolomics in the field of medical research have significantly enhanced our comprehension of metabolites as functional intermediaries in disease pathogenesis [6], [7]. In recent years, the concept of 'Genetically Determined Metabolotypes' (GDMs) has been introduced to deepen the understanding of the interplay between genetic variations and environmental triggers of diseases [8], [9]. GDMs, which reflect both the cellular function and physiological states, may unravel metabolic pathway abnormalities associated with vitiligo, thus offering novel strategies for treating and managing the condition. Hence, it is imperative to conduct comprehensive analyses on these lines to illustrate the causal relationships between GDMs and vitiligo and to understand their potential mediating roles.

Mendelian randomization (MR) is an epidemiological method that enhances causal inferences based on genetic variation [10]. This method boasts several advantages. Firstly, MR findings are less susceptible to confounding factors given that genetic variation is randomly assigned at the start and is independent of environmental and lifestyle factors. Furthermore, MR reduces the possibility of reverse causality since germline genotypes are not influenced by disease onset and progression [11]. To our knowledge, no study till date has systematically assessed the relationship between vitiligo and autoimmune diseases using MR. Moreover, our objective is to identify key blood metabolites that may play a significant role in disease pathogenesis by integrating metabolomics with genomics data. In this study, we utilized a two-sample MR approach to assess the reciprocal relationship between vitiligo and the risk of autoimmune diseases. Subsequently, we employed a two-sample MR approach to assess the causal relationship between GDMs and vitiligo to identify key metabolic pathways involved in the occurrence and development of the disease. Besides two-sample MR analysis, our research also included a multivariable MR (MVMR) analysis, systematically evaluating the potential mediating roles of GDMs in the progression of vitiligo and associated autoimmune diseases (Fig. 1).