SPP1 (osteopontin): a key regulator orchestrating cancer progression and non-cancerous pathologies - therapeutic opportunities and future directions

Sep 22, 2026

Secreted Phosphoprotein 1 (SPP1), also known as osteopontin, is a multifaceted matricellular glycoprotein that drives diverse biological processes through integrin and CD44 receptor signaling. Evidence links SPP1 to tumor progression and metastasis and to major non-cancer conditions such as pregnancy-related complications, fibrotic disorders, and neurological diseases. The review explains how SPP1 functional pleiotropy regulates angiogenesis, epithelial-mesenchymal transition, and immunosuppression, advancing disease progression. It synthesizes current mechanistic insights and therapeutic opportunities while emphasizing safe, precision-targeted interventions.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

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1 Introduction

Secreted phosphoprotein 1 (SPP1) as osteopontin and its biological roles

Mechanistic basis: receptors, motifs, and downstream signaling

SPP1 in tumors: proliferation, apoptosis, invasion, metastasis, and microenvironment

SPP1 in immunity: macrophages and MDSCs

SPP1 in non-cancerous pathologies: pregnancy, fibrosis, inflammation, and tissue remodeling

OPEN ACCESS EDITED BY Hongbiao Huang, Children’s Hospital of Soochow University, China REVIEWED BY Sefa Erturk, Nigde Omer Halisdemir University Faculty of Medicine, Türkiye Fan Lin, Fujian Provincial Hospital, China *CORRESPONDENCE Cong Hu, [conghu@jlu.edu.cn](conghu@jlu.edu.cn) RECEIVED 18 June 2026 REVISED 13 July 2026 ACCEPTED 15 July 2026 PUBLISHED 05 August 2026 CITATION Pang B, Sun H, Ouyang M and Hu C (2026) SPP1 (osteopontin): a key regulator orchestrating cancer progression and non-cancerous pathologies-therapeutic opportunities and future directions. Front. Cell Dev. Biol. 14:1912468 . doi: 10.3389/fcell.2026.1912468 COPYRIGHT © 2026 Pang, Sun, Ouyang and Hu. This isan open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Review PUBLISHED 05 August 2026 DOI 10.3389/fcell.2026.1912468 SPP1 (osteopontin): a key regulator orchestrating cancer progression and non-cancerous pathologies-therapeutic opportunities and future directions Bo Pang 1, Huan Sun 2, Mingyu Ouyang 3 and Cong Hu 4* 1Cardiology Department, First Hospital of Jilin University, Changchun, Jilin, China, 2Electrodiagnosis Department, Qianwei Hospital of Jilin Province, Changchun, China, 3Department of Reproductive Medicine, Hezhou People’s Hospital of Guangxi Zhuang Autonomous Region, Hezhou, China, 4Reproductive Medicine Center, Prenatal Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, China Secreted Phosphoprotein 1 (SPP1) is a multifaceted matricellular glycoprotein that mediates diverse biological processes via integrin and CD44 receptor signaling. While its profound contributions to tumor progression and metastasis are extensively documented, emerging evidence underscores its pivotal roles across diverse non-cancerous conditions, including pregnancy-related complications, fibrotic diseases and neurological disorders. Crucially, SPP1 exhibits functional pleiotropy, orchestrating angiogenesis and epithelialmesenchymal transition, while modulating immunosuppression. These collective actions drive disease progression, establishing SPP1 as a compelling therapeutic target. This review synthesizes current understanding of SPP1 biology, highlighting mechanistic insights imperative for translating its therapeutic potential into safe, precision-targeted interventions against diverse SPP1-driven pathologies. KEYWORDS angiogenesis, epithelial-mesenchymal transition, pregnancy, secreted phosphoprotein 1, tumor 1 Introduction Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN), is amultifunctional phosphorylated glycoprotein that has emerged as a pivotal molecule in a wide array of physiological and pathological processes (Yan et al., 2023). Initially identified as a bone matrix protein crucial for osteoclast attachment and bone remodeling, SPP1 is now widely recognized as a versatile cytokine and extracellular matrix component. It is expressed by numerous cell types, including osteoblasts, macrophages, T cells, endothelial cells, and various cancer cells (Ellert-Miklaszewska et al., 2025; Li et al., 2025; Gao et al., 2022) . Structurally, SPP1 contains an arginine-glycine-aspartate motif that mediates binding to several integrins, as well as a CD44-interacting domain, enabling it to engage a wide range of cell surface receptors and activate context-dependent downstream signaling pathways (Hou et al., 2025) . The structural versatility underpins the capacity of SPP1 to regulate cell adhesion, migration, survival, and differentiation across different biological contexts (Jiang et al.

FAQs

What is SPP1 (osteopontin) and how does it signal?

SPP1 is a multifaceted matricellular glycoprotein that mediates biological processes via integrin and CD44 receptor signaling. Its structure includes motifs that enable binding to cell-surface receptors and activation of context-dependent downstream pathways.

How does SPP1 contribute to cancer progression and metastasis?

SPP1 promotes malignant progression by enhancing proliferation, inhibiting apoptosis, increasing invasion and metastasis, and modulating the tumor microenvironment. SPP1+ immune subsets such as macrophages and MDSCs are associated with immunosuppression and poor prognosis.

What roles does SPP1 play in non-cancerous conditions?

SPP1 functions in pregnancy-related biology, including embryo implantation, maternal-fetal communication, and placental development. Aberrant SPP1 signaling is also linked to fibrotic diseases, chronic inflammation, and pathological tissue repair.

Sep 22, 2026

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