Spatial transcriptomics uncovers lipid metabolic dysregulation driving immune-stroma crosstalk in Sjögren's Disease

Shasha Li; Yan Liu; Haoshan Zhang; Simin Xu; Xiuzhen Wen; Yanhua Tang; Nana Zhang; David A Fox; Yanming Chen; Yunfeng Pan; Chenyang Lu

doi:10.1016/j.ebiom.2025.106074

Spatial transcriptomics uncovers lipid metabolic dysregulation driving immune-stroma crosstalk in Sjögren's Disease

EBioMedicine. 2026 Jan:123:106074. doi: 10.1016/j.ebiom.2025.106074. Epub 2025 Dec 17.

Authors

Shasha Li¹, Yan Liu², Haoshan Zhang³, Simin Xu², Xiuzhen Wen⁴, Yanhua Tang⁴, Nana Zhang⁵, David A Fox⁶, Yanming Chen⁷, Yunfeng Pan⁸, Chenyang Lu⁹

Affiliations

¹ Division of Rheumatology, Department of Internal Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China.
² Division of Rheumatology, Department of Internal Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China.
³ Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China.
⁴ Rheumatology and Immunology Department, Jiujiang City Key Laboratory of Cell Therapy, Jiujiang NO.1 People's Hospital, Jiujiang, Jiangxi, China.
⁵ Department of Pathology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China.
⁶ Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China. Electronic address: chyanm@mail.sysu.edu.cn.
⁸ Division of Rheumatology, Department of Internal Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China. Electronic address: panyunf@mail.sysu.edu.cn.
⁹ Division of Rheumatology, Department of Internal Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, China. Electronic address: luchy29@mail.sysu.edu.cn.

Abstract

Background: Sjögren's Disease (SjD) is a systemic autoimmune disorder characterised by exocrine gland dysfunction and immune infiltration. However, the spatial cellular architecture and metabolic-immune crosstalk underlying glandular pathology in SjD remain unclear.

Methods: We performed spatial transcriptomics on SjD salivary glands (SGs) and conducted integrative analyses with single-cell RNA sequencing to delineate disease-specific transcriptomic alterations, followed by validation in an independent cohort. Key findings were verified via immunofluorescence, immunohistochemistry, and function assays on cells.

Findings: Spatial clustering revealed distinct perturbations in SjD. We identified a pathogenic CCL2^high fibroblast-ACKR1^high endothelial cell axis that co-localised in lymphoid foci and correlated with immune infiltration and disease activity. Chemokine-receptor axes were associated with immune infiltration, with endothelial ACKR1 facilitating inflammatory niche organisation. Compartmentalised immune-stroma niches exhibited upregulated phospholipid, glycerophospholipid and phosphatidylinositol metabolism in lymphoid foci, correlating with B/T-cell activation and interferon responses. Key metabolic regulators (PIK3CD, PIK3CG, PIKFYVE, and PLCG2) were elevated in SjD, associated with CD45⁺ cell abundance in SGs, and exhibited diagnostic potential. Conversely, epithelial cells showed suppressed glycerolipid metabolism and decreased MGLL expression, linked to enhanced antigen presentation. Inhibiting monoacylglycerol lipase (encoded by MGLL) upregulates MHC in A253 cells, while interferon-γ suppresses MGLL expression.

Interpretation: Our study elucidates spatially organised metabolic-immune networks in SjD, implicating lipid metabolism in immune activation and epithelial metabolic reprogramming in secretory dysfunction, nominating promising therapeutic targets.

Funding: National Natural Science Foundation of China (82104484,32301084), Joint funding from schools (colleges) and enterprises in Guangzhou (2025A03J3203, 2024A03J0987), Natural Science Foundation of Guangdong Province (2023A1515012790), Guangdong Provincial Enterprise Joint Fund (2022A1515220003), and Sun Yat-sen University (P02523).

Keywords: Lymphoid foci; Metabolism; Salivary gland; Sjögren's disease; Spatial transcriptomics.

MeSH terms

Female
Gene Expression Profiling
Humans
Lipid Metabolism* / genetics
Male
Salivary Glands / immunology
Salivary Glands / metabolism
Salivary Glands / pathology
Sjogren's Syndrome* / etiology
Sjogren's Syndrome* / genetics
Sjogren's Syndrome* / immunology
Sjogren's Syndrome* / metabolism
Sjogren's Syndrome* / pathology
Stromal Cells* / immunology
Stromal Cells* / metabolism
Transcriptome*