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A MIF-p38-GSDMD inflammatory loop in keratinocytes underlies UVB-induced cutaneous lupus
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  • Published: 02 February 2026

A MIF-p38-GSDMD inflammatory loop in keratinocytes underlies UVB-induced cutaneous lupus

  • Chipeng Guo  ORCID: orcid.org/0000-0003-3967-57531,
  • Siweier Luo2,
  • Jigang Luo3,
  • Siyao Lu1,
  • Xiaomei You1,
  • Junlin Cao2,
  • Yufei Du2,
  • Haoran Lv4,
  • Hanzhi Liang4,
  • Le Wang2,
  • Liangchun Wang1,
  • Tao Liu3 &
  • …
  • Yiming Zhou  ORCID: orcid.org/0000-0002-2109-43201,2 

Cell Death & Disease , Article number:  (2026) Cite this article

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Subjects

  • Autoimmune diseases
  • Autoimmunity

Abstract

Ultraviolet B (UVB) is a well-recognized trigger of cutaneous lupus erythematosus (CLE), yet its molecular basis remains largely undefined. Here, using single-cell transcriptomics and a lupus-prone mouse model, we identify keratinocyte-derived macrophage migration inhibitory factor (MIF) as a key amplifier of cutaneous inflammation through a self-sustaining feedback loop. Single-cell RNA sequencing reveals elevated MIF expression specifically within pathogenic, interferon-high keratinocyte subclusters associated with CLE, which is further validated across major CLE subtypes in clinical skin samples. In vitro, UVB irradiation dose-dependently induces the release of MIF from keratinocytes, which in turn promotes inflammatory signaling and matrix remodeling in both keratinocytes and fibroblasts. Mechanistically, we demonstrate that UVB irradiation activates the ribotoxic stress response (RSR), leading to the p38-C/EBPβ-mediated transcriptional upregulation of NLRP3 and GSDMD cleavage in keratinocytes. The ensuing GSDMD-dependent pyroptosis facilitates the release of MIF, primarily through GSDMD pores rather than vesicular secretion, which in turn amplifies the p38-C/EBPβ signaling pathway. Therapeutic disruption of this loop either by gene silencing via AAVs or pharmacological inhibition via microneedles, markedly attenuates epidermal hyperplasia and cytokine imbalance in lupus-prone mice. These findings uncover a previously unrecognized MIF-p38-GSDMD inflammatory loop contributes to the UVB-induced cutaneous lupus, offering both mechanistic insights and translational opportunities for CLE.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. This study involved the re-analysis of publicly available single-cell RNA sequencing data from GEO under accession number GSE186476. All of the data can be found in either the main text or the supplementary materials.

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Acknowledgements

We are deeply grateful to Professor Tao Liu and his research group for their expert contribution and collaboration in the engineering of the dissolvable microneedle patches. Furthermore, we sincerely acknowledge the dedicated staff at the Basic and Translational Medical Research Center of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, for providing critical platform resources and technical support throughout this project.

Funding

This work was supported by the following grants: National Natural Science Foundation of China Grant No. 81970632 (YZ, Guangzhou), National Natural Science Foundation of China Grant No. 81872524, 82073431 (LW, Guangzhou), Guangdong Science and Technology Department Grant No. 2020B1212060018 and 2020B1212030004 (YZ, Guangzhou), Sun Yat-sen Pilot Scientific Research Fund Grant No. YXQH202415 (CG, Guangzhou).

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Authors and Affiliations

  1. Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Chipeng Guo, Siyao Lu, Xiaomei You, Liangchun Wang & Yiming Zhou

  2. Basic and Translational Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Siweier Luo, Junlin Cao, Yufei Du, Le Wang & Yiming Zhou

  3. Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China

    Jigang Luo & Tao Liu

  4. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Haoran Lv & Hanzhi Liang

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Contributions

YZ, CG, and TL designed the experiment. CG, LW, and YZ funded the experiment. CG, SL, XY, JC, YD, HL, HL, and LW performed the in vitro and in vivo experiments, analyzed and generated data. SL performed the bioinformatics analysis of scRNA-seq data. TL and JL fabricated the microneedle patches. All authors participated writing and approved the manuscript.

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Correspondence to Chipeng Guo, Liangchun Wang, Tao Liu or Yiming Zhou.

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Supplementary Materials

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Full scans of Western blots

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Guo, C., Luo, S., Luo, J. et al. A MIF-p38-GSDMD inflammatory loop in keratinocytes underlies UVB-induced cutaneous lupus. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08443-4

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  • Received: 16 July 2025

  • Revised: 08 December 2025

  • Accepted: 21 January 2026

  • Published: 02 February 2026

  • DOI: https://doi.org/10.1038/s41419-026-08443-4

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