A lipid "switch" in the bone marrow: how LPC (16:0/0:0) drives immune thrombocytopenia—and how a two-drug combination turns it off

Immune thrombocytopenia (ITP) is characterized by autoimmune-mediated platelet destruction and impaired platelet production, with macrophages playing a central role as both antigen-presenting cells and platelet-phagocytosing effectors. Although glucocorticoids such as dexamethasone (DXM) remain the first-line therapy, roughly one-third of patients develop resistance or experience relapse. Traditional research has focused largely on intrinsic immune-cell dysfunction, yet the metabolic underpinnings of macrophage dysregulation in ITP have remained unclear. 

To address this gap, a team led by Professor Yan Liu and Associate Professor Shuwen Wang from the Department of Hematology, Qilu Hospital of Shandong University, China, investigated whether a specific metabolite could be driving macrophage dysfunction in ITP. Their findings were published in Chinese Medical Journal on September 14, 2026.  

The researchers performed untargeted metabolomics and transcriptomics on bone marrow mononuclear cell-derived macrophages from 61 patient with ITP and 46 healthy controls. Integrated analysis of 1,755 metabolites and 26,055 genes revealed significant enrichment of the glycerophospholipid metabolic pathway—particularly lysophosphatidylcholine (LPC) metabolism. Among all LPC species, LPC (16:0/0:0) emerged as the most significantly elevated metabolite, with levels markedly higher in both bone marrow supernatants and plasma of patients with ITP compared with controls. Critically, LPC (16:0/0:0) concentrations correlated inversely with platelet counts and were especially high in patients with severe disease, with platelet counts below 30 × 10⁹/L. 

Functional experiments confirmed the pathogenic role of LPC (16:0/0:0). In vitro, the lipid polarized macrophages toward the pro-inflammatory M1 phenotype, suppressed interleukin-10 (IL-10) expression and secretion at both mRNA and protein levels, upregulated the phagocytic receptor CD16 (FcγRIII), and significantly enhanced macrophage phagocytosis of platelets. It also disrupted T-cell homeostasis by reducing regulatory T-cell proportions and promoting Th1/Th2 differentiation. Mechanistically, the G protein-coupled receptor 68 (GPR68) was implicated: pretreatment with the GPR68-specific inhibitor Ogeromorphin effectively reversed LPC-induced IL-10 suppression and macrophage polarization, identifying GPR68 as a key downstream mediator of LPC-driven immune dysregulation. 

Building on these mechanistic insights, the team tested a "drug repurposing" combination strategy: DXM, a classic immunosuppressant, paired with atorvastatin (AT), a lipid-metabolism modulator. In both passive and active ITP mouse models, the DXM + AT combination outperformed either drug alone, producing faster and more complete platelet count recovery. The two agents acted through complementary mechanisms: AT focused on "upstream metabolic regulation," lowering LPC levels and restoring Treg proportions by modulating the lipid metabolic environment, while DXM provided "downstream immune suppression," inhibiting aberrant macrophage activation and pro-inflammatory Th1/Th2 differentiation. Together, they more effectively repolarized macrophages from M1 toward the anti-inflammatory M2 phenotype and restored bone marrow IL-10 levels. 

“This study identifies LPC (16:0/0:0) as a novel metabolic driver of immune dysregulation in ITP and proposes a dual-target strategy that combines metabolic correction with immune suppression,” explains Prof. Liu. “Because both DXM and AT are already widely used in clinical practice with well-established safety profiles, this combination has strong translational potential for steroid-resistant or relapsed patients with ITP.” Assoc. Prof. Wang adds: “Our findings shift the perspective from purely immune-cell-centric views toward immunometabolism, which may also inform the treatment of other autoimmune disorders.” 

The authors note that further randomized controlled trials are needed to evaluate the long-term efficacy and safety of the DXM–AT combination in steroid-resistant patients with ITP. Nevertheless, the study opens a promising new avenue for overcoming one of the most persistent challenges in ITP management. 
 

Reference 
Title of original paper: Lysophosphatidylcholine-induced macrophage polarization imbalance and functional dysregulation in immune thrombocytopenia  
Journal: Chinese Medical Journal  
DOI: https://doi.org/10.1097/CM9.0000000000004172  

About Associate Professor Shuwen Wang from Qilu Hospital of Shandong University 
Dr. Shuwen Wang is an Associate Researcher in the Department of Hematology at Qilu Hospital of Shandong University. Her research focuses on the pathogenesis and treatment of immune thrombocytopenia. She has published papers as first or corresponding author in journals including Blood, Signal Transduction and Targeted Therapy, Cellular & Molecular Immunology, and Metabolism. She has led multiple research projects including a General Program of the National Natural Science Foundation of China. She serves as a member of the Laboratory Diagnostics Group of the Hematology Branch, Chinese Medical Association, and a Youth Committee member of the Experimental Hematology Committee, Chinese Pathophysiology Society. 

About Professor Yan Liu from Qilu Hospital of Shandong University  
Professor Yan Liu is an Assistant Researcher in the Department of Hematology at Qilu Hospital of Shandong University. She has led a Youth Program of the National Natural Science Foundation of China, a General Program of China Postdoctoral Science Foundation, and a Youth Program of the Natural Science Foundation of Shandong Province. She was selected for the Shandong Province Postdoctoral Innovative Talent Support Program. Dr. Liu has published SCI papers on thrombocytopenia as a first or co-first author in journals including Blood and Signal Transduction and Targeted Therapy. She serves on the Hematopoietic Reconstruction and Cell Engineering Committee of the Shandong Stem Cell Society. 

Funding information 
This work was supported by grants from the National Natural Science Foundation of China (Nos. 823B2003, 8220138, 82400161, 82400162, 82300130), the Taishan Scholar Foundation of Shandong Province (Nos. tsqn202306350 and tsp20221157), the Natural Science Foundation of Shandong Province (No. ZR2022QH081), and the National Key Research and Development Program of China (No. 2023YFC2507800).