《生命科学》 2026, 38(10): 1791-1803

鞘磷脂代谢和调控机制及其疾病关联研究进展

房洋^1,2 , 白露^1,2 , 郭澄¹ , 王广川³ , 杨全军^1,2,*

¹上海交通大学医学院附属第六人民医院药剂科，上海 200233 ²东华大学生物与医学工程学院，上海 201620 ³中国科学院分子细胞科学卓越创新中心，多细胞体系结构与功能重点实验室，上海 200031

摘　要：

鞘磷脂（sphingomyelin， SM）是哺乳动物细胞膜的关键结构组分，其生物活性代谢物——神经酰胺（ceramide，Cer）和1-磷酸鞘氨醇（sphingosine-1-phosphate，S1P）在细胞增殖、凋亡及免疫应答等生命活动中发挥多种调控作用。SM代谢包括从头合成、分解代谢及补救途径，涉及丝氨酸棕榈酰基转移酶（serine palmitoyltransferase，SPT）、神经酰胺合成酶（ceramide synthase，CERS）、鞘磷脂合成酶（sphingomyelin synthase，SMS）、鞘磷脂酶（sphingomyelinase，SMase）和鞘氨醇激酶（sphingosine kinase，SPHK）等关键酶。这些酶的活性受到转录调控、翻译后修饰及代谢产物反馈等多维度的精密调节。近年研究表明，SM代谢紊乱与肿瘤、免疫炎症、代谢性疾病、神经退行性疾病和心血管疾病等多种疾病密切相关。本文系统梳理了SM的代谢途径、关键酶的功能及其调控机制；重点阐述其代谢物的动态平衡及其在肿瘤、免疫炎症、代谢性疾病、神经退行性疾病和心血管疾病中的作用及病理价值；总结针对SM代谢关键酶（如SMS、SMase、SPHK等）的靶向治疗策略及其临床前与临床研发进展。

通讯作者：杨全军 , Email:myotime@sjtu.edu.cn

Research progress on sphingomyelin metabolism, its regulatory mechanisms, and disease associations

FANG Yang^1,2 , BAI Lu^1,2 , GUO Cheng¹ , WANG Guang-Chuan³ , YANG Quan-Jun^1,2,*

¹Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China ²College of Biological and Medical Engineering, Donghua University, Shanghai 201620, China ³Key Laboratory of Multicellular Structure and Functional Studies, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China

Abstract:

Sphingomyelin (SM) is a major structural phospholipid in mammalian cell membranes and serves as a central hub in sphingolipid metabolism. SM not only maintains membrane integrity and organization, but also generates multiple bioactive metabolites, most notably ceramide (Cer) and sphingosine-1-phosphate (S1P), which exert pleiotropic and often opposing effects on cell survival, apoptosis, proliferation, inflammation, and immune responses. Increasing evidence has established that disruption of SM metabolic homeostasis is closely associated with the pathogenesis of a wide range of human diseases. SM metabolism comprises de novo synthesis, catabolic degradation, and salvage pathways, coordinated by a series of key enzymes, including serine palmitoyltransferase (SPT), ceramide synthase (CerS), sphingomyelin synthase (SMS), sphingomyelinase (SMase), and sphingosine kinase (SPHK). The activity and expression of these enzymes are regulated through multiple layers of control, including transcriptional regulation, post-translational modification, subcellular compartmentalization, and feedback modulation by metabolic intermediates. Such regulation is essential for maintaining the dynamic balance among SM, Cer, and key downstream metabolites, thereby shaping downstream signaling networks and cellular fate decisions. Accumulating studies have highlighted the pathological relevance of dysregulated SM metabolism in cancer, immune and inflammatory disorders, metabolic diseases, neurodegenerative diseases, and cardiovascular diseases. In these settings, altered sphingolipid flux contributes to aberrant signaling, organelle dysfunction, inflammatory remodeling, and disease progression. Particular attention has also been directed toward the therapeutic potential of targeting critical metabolic nodes, such as SMS, SMase, and SPHK, with several candidate interventions showing promise in preclinical and early clinical studies. Continued advances in lipidomics, structural biology, spatial omics, genome editing, and artificial intelligence-assisted drug discovery are expected to accelerate mechanistic dissection and translational exploitation of SM metabolism. A deeper understanding of SM metabolic regulation may provide novel opportunities for disease diagnosis, prevention, and targeted intervention.

Communication Author：YANG Quan-Jun , Email:myotime@sjtu.edu.cn