On March 5, 2026 (Beijing Time), teams led by Professor Lu Qianjin (Institute of Dermatology, Chinese Academy of Medical Sciences), Professor Wu Haijing (The Second Xiangya Hospital of Central South University & Furong Laboratory), in collaboration with Professor Wanli Liu (School of Life Sciences, Tsinghua University) and Professor Yonghui Zhang (School of Pharmaceutical Sciences, Tsinghua University), published an original research article in the international peer-reviewed journal Nature entitled “A metabolic alarmin from keratinocytes potentiates systemic humoral immunity”. A related study entitled “Fragrant TRPV3 agonists act as titratable organic adjuvants to amplify antigen-specific IgG response” was simultaneously published in Immunity & Inflammation.

This study reveals a novel mechanism whereby farnesyl pyrophosphate (FPP), a metabolic intermediate of the mevalonate pathway derived from keratinocytes (KC), functions as an endogenous metabolic alarmin. FPP rapidly and potently activates the TRPV3 channel from local lesions, triggering the Ca²⁺–CaM–calcineurin–NFAT and PYK2–RAS–ERK signaling cascades to regulate systemic humoral immune responses.

Notably, the study further demonstrates that exogenous aromatic TRPV3 agonists of medicinal plant origin—including carvacrol and camphor—similarly amplify antigen-specific antibody responses via the TRPV3–Ca²⁺ signaling axis.This dual-mode TRPV3 activation system, consisting of complementary endogenous metabolic alarmins and exogenous sensory aromatic compounds, provides potential targets and strategies for the development of novel vaccine adjuvants and the prevention and treatment of autoimmune diseases such as systemic lupus erythematosus (SLE).

How local infection or stimulation triggers systemic humoral immune responses has long been a key challenge in immunology. Humoral immunity relies on germinal center (GC) reactions, which involve the differentiation of follicular helper T (Tfh) cells, Bcell proliferation, and affinity maturation to generate hightiter, highaffinity IgG antibodies and memory B cells that provide longlasting protection. As the outermost cells of the skin, keratinocytes (KCs) not only serve as a physical barrier but also sense external “threats” and initiate and coordinate immune defense responses, acting as a critical link between innate and adaptive immunity. When local infection or external stimulation occurs in the skin, damageassociated molecular patterns (DAMPs) are released to modulate immune responses. However, the critical scientific question of how locally generated immune signals are precisely transmitted to activate systemic humoral immunity and ultimately induce specific antibody production to defend against deeper pathogen invasion and control infection has long remained incompletely resolved.In recent years, metabolic intermediates have emerged as a new class of DAMPs, termed metabolismassociated molecular patterns (MAMPs), and play important roles in immune regulation. The mevalonate pathway is a core cellular metabolic pathway, whose isoprenoid intermediates participate in diverse physiological processes. Yet whether it contributes to the regulation from local skin immunity to systemic humoral immunity, as well as its underlying molecular mechanisms and pathophysiological significance, remains largely unknown.Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease. Patients with SLE often exhibit abnormally increased colonization by Staphylococcus aureus in skin lesions, accompanied by aberrantly activated humoral immunity and excessive production of autoantibodies that attack host tissues and organs. Nevertheless, whether and how local immune dysregulation in the skin triggers systemic autoimmune responses remains a critical issue urgently to be addressed in both clinical and basic research. Elucidating the immune regulatory pathways mediated by local skin metabolites will not only help uncover the molecular mechanisms by which local infection elicits systemic humoral immune responses, but also provide a novel perspective for understanding the pathogenesis of autoimmune diseases such as SLE, while laying an important theoretical foundation for the development of novel vaccine adjuvants and therapeutic drugs for autoimmune diseases.

To address these key scientific questions, Professor Wanli Liu’s team, in collaboration with teams led by Professors Qianjin Lu and Haijing Wu, conducted an interdisciplinary study. Using multiple approaches including metabolomics, singlecell sequencing, molecular biology, and animal models, the researchers systematically identified farnesyl pyrophosphate (FPP) as an endogenous immune alarmin derived from keratinocytes (KCs). They further delineated the FPP–TRPV3–IL6/CCL20–GC signaling axis that regulates systemic humoral immunity (Figures 1 and 2).Meanwhile, the study revealed that aromatic TRPV3 agonists such as carvacrol and camphor can act as adjuvants to enhance antibody responses via the TRPV3–Ca²⁺ signaling axis (Figure 2). These findings uncover a novel molecular mechanism by which local infection triggers systemic humoral immune responses.In addition, FPP was found to exert acute, local, and tissuespecific effects: it only functions as an adjuvant when injected intradermally at the same site as the antigen, and is rapidly degraded by endogenous phosphatases into inactive farnesyl monophosphate (FMP). This property provides an important safety basis for the development of FPP as a vaccine adjuvant.

To explore the clinical implications of this mechanism, the research team focused on systemic lupus erythematosus (SLE), a prototypical autoimmune disease. Single-cell RNA sequencing analysis of skin lesions from SLE patients revealed that the unfolded protein response (UPR)–mevalonate pathway was aberrantly activated in keratinocytes (KCs), particularly in the TRPV3-highly expressing KC subset. The FPP–TRPV3–IL6/CCL20 signaling axis was hyperactivated, and the activation level of this pathway was positively correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI).

Further animal experiments demonstrated that Staphylococcus aureus colonization exacerbated lupus-like pathologies in mice by activating this signaling axis. Exogenous FPP treatment significantly increased anti-dsDNA autoantibody titers and urinary protein levels in lupus-prone mice, aggravating renal injury. In contrast, keratinocyte-specific TRPV3 knockout effectively alleviated FPP-mediated lupus exacerbation.

Moreover, the research team validated the potential value of this signaling axis in vaccine development. FPP, when used as an adjuvant in combination with influenza hemagglutinin protein or pneumococcal vaccine, markedly elevated vaccine-induced specific IgG titers. This led to greatly improved survival rates, as well as significantly reduced pathological symptoms and body weight loss in mice challenged with influenza virus or Streptococcus pneumoniae. These results indicate that FPP holds great potential for development as a novel vaccine adjuvant. Similarly, exogenous agonists such as carvacrol and camphor enhanced IgG responses through analogous mechanisms.

In summary, this study identifies a novel function of the metabolic intermediate FPP as an endogenous alarmin derived from keratinocytes, delineates the molecular pathway by which local skin signals regulate systemic humoral immunity, and addresses the key scientific question of how local infection triggers systemic antibody responses. This work also reveals a critical role for the FPP–TRPV3 axis in the pathogenesis and progression of SLE, demonstrating that hyperactivation of this signaling axis drives autoimmune dysregulation and provides novel potential targets for the treatment of SLE and other autoimmune diseases, including TRPV3, IL6, and CCL20.

Furthermore, the acute and local adjuvant effects of FPP open new avenues for the development of next-generation vaccine adjuvants, with promising application prospects especially in mucosal immunity and anti-infective vaccines. By integrating metabolic regulation with skin immunity and humoral immunity, this study provides a new perspective for understanding the crosstalk in immunometabolism and lays an important theoretical foundation for translational research in immune-related diseases.

For the Nature paper:Professor Qianjin Lu from the Hospital for Skin Diseases, Chinese Academy of Medical Sciences, and the Second Xiangya Hospital, Central South University; Professor Yonghui Zhang and Professor Wanli Liu from Tsinghua University are the co-corresponding authors.Dr. Zhenglin Ji, Doctoral Candidate Ji Gao, Dr. Shaocun Zhang, Doctoral Candidate Jiajie Li from Tsinghua University; Professor Haijing Wu from the Second Xiangya Hospital, Central South University & Furong Laboratory; Doctoral Candidate Jing Yao from Zhejiang University; Dr. Xianqiang Ma from Tsinghua University; Doctoral Candidate Yue Xin from the Second Xiangya Hospital, Central South University; Dr. Yongjie Zhu and Dr. Meng Zhao from Tsinghua University are the co-first authors.This study was supported by Professor Rong Xiao, Dr. Zhidan Zhao, Doctoral Candidate Kai Shen, and Associate Researcher Ming Yang from the Second Xiangya Hospital, Central South University.

For the paper in Immunity & Inflammation:Professor Qianjin Lu from the Hospital for Skin Diseases, Chinese Academy of Medical Sciences; Professor Haijing Wu from the Second Xiangya Hospital, Central South University & Furong Laboratory; and Professor Wanli Liu from Tsinghua University are the co-corresponding authors.Dr. Zhenglin Ji, Doctoral Candidate Ji Gao from Tsinghua University, and Doctoral Candidate Yue Xin from the Second Xiangya Hospital, Central South University are the co-first authors.

The joint research team was supported by grants from the National Natural Science Foundation of China, the National Key Research and Development Program, the Chinese Academy of Medical Sciences Fund, the Major Research Program for High-Level Health Talents of the Hunan Provincial Health Commission, and other funding agencies.

Source from The second xiangya hospital of central south university