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Hyaluronan (HA), a major glycocalyx component, is known to affect membrane morphology, but its role in MP regulation through glycocalyx reconstruction remains unclear. This study links HA-related glycocalyx (HA-GCX) thickness to enhanced MP activity; HA-GCX disruption reduces ruffle formation and suppresses MP. HA-GCX removal increases CDKN1A/p21 and downstream MMP1/9, and p21/MMP knockdown restores MP, while HA-GCX digestion delays tumor growth in vivo, indicating a therapeutic avenue.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/impairment-of-hyaluronan-related-glycocalyx-inhibits-macropinocytosis-in-cancer-cells-via-p21-upregulation/373795/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/impairment-of-hyaluronan-related-glycocalyx-inhibits-macropinocytosis-in-cancer-cells-via-p21-upregulation/373795.png","ImageObject",300,407,{"name":92,"@type":93},"Fans","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-24","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does HA-related glycocalyx (HA-GCX) influence macropinocytosis in cancer cells?","Question",{"text":112,"@type":113},"HA-GCX thickness is positively correlated with macropinocytosis activity. Disrupting HA-GCX suppresses MP by decreasing membrane ruffle formation.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What molecular changes occur after HA-GCX removal?",{"text":117,"@type":113},"HA-GCX removal upregulates CDKN1A/p21 and its downstream targets MMP1/9. Knockdown of p21 or MMP1/9 can rescue macropinocytosis.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the evidence that HA-GCX breakdown can affect tumor growth in vivo?",{"text":121,"@type":113},"The study reports that HA-GCX digestion delays tumor growth in vivo by inhibiting the p21-MMP1/MMP9 axis-mediated MP.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},373795,1790813118,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},5909892330395,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","This article is licensed under CC-BY 4.0   \n[pubs.acs.org/Biomac](pubs.acs.org/Biomac)  Article   \nImpairment of Hyaluronan-Related Glycocalyx Inhibits Macropinocytosis in Cancer Cells via p21 Upregulation  \nGuangxin Luan,† Qian Guo,† Yiwen Liu, Guoliang Zhang, Yan Du, Cuixia Yang, Hui Wang, Jiajie Hu, Yiqing He, * and Feng Gao*  \n Cite This: Biomacromolecules 2025, 26, 6586−6599  \nRead Online  \n\n|  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- |\n| ACCESS   | Metrics & More |  |  Article Recommendations |  | *sı Supporting Information |\n\nABSTRACT: Macropinocytosis (MP) in cancer cells is an endocytic process for nutrient extraction initiated by membrane ruffling that supports tumor progression. Hyaluronan (HA), a major component of glycocalyx coating the surface of living cells, is reported to influence the membrane morphology. However, whether HA-related glycocalyx (HA-GCX) regulates MP through membrane reconstruction remains unclear. Here, we demonstrated that the HA-GCX thickness was positively correlated with MP activity in cancer cells. Intriguingly, the disruption of HA-GCX could suppress MP by decreasing membrane ruffle formation. Furthermore, the knockdown of cyclin-dependent kinase inhibitor 1 (CDKN1A/p21) and its downstream matrix metalloproteinase (MMP) 1/9, which were identified to be significantly upregulated  \nfollowing HA-GCX removal, could rescue MP. Importantly, the breakdown of HA-GCX could impede cancer cell proliferation through inhibition of MP. Taken together, our study revealed a novel regulatory role of HA-GCX in MP, which might provide a promising therapeutic avenue in cancer treatment.  \n1. INTRODUCTION  \nMacropinocytosis (MP) is a highly conserved endocytic process for nonselective internalization of extracellular nutrients in cancer cells and ingestion of pathogens in phagocytes.1 MP is characterized by the formation ofplasma membrane ruffles and the subsequent generation of large-sized vesicles called macropinosomes.2 It is reported that the extracellular matrix (ECM) is the main source of macromolecules for cancer cells to obtain energy under a nutrient-poor environment through MP.3 For example, hyaluronan (HA), a major ECM glycosaminoglycan, could be internalized by MP under nutrient deprivation.4 Furthermore, studies demonstrate that proline, a key amino acid liberated from collagen degradation, is taken up via MP and serves as a crucial energy source and biosynthetic precursor to enhance cancer cell survival.5 During cancer progression, ECM components and construction undergo remodeling both within the tumor stroma and cancer cell membrane including glycocalyx.6  \nGlycocalyx is a gel-like pericellular meshwork coating living cells, which comprises glycoproteins, glycolipids, proteoglycans, and glycosaminoglycans.7 In cancer cells, the composition and structure of the glycocalyx changed markedly, leading to an increase in glycocalyx thickness.8 It is demonstrated that malignant cancer cells present a denser HA coat, a major component of glycocalyx located at the outer surface of the cell membrane that is implicated in cancer progression such as  \nproliferation, metastasis, and drug resistance.9 A previous study has reported that HA polymers in the glycocalyx could regulate the membrane shape, such as the extension of spherical and tubular membrane structures.10 Meanwhile, the generation of macropinosomes in MP was found to be dependent on the cellular membrane deformation like ruffles.11 Thus, this promptsus to speculate that the HA-related glycocalyx (HA-GCX) might be closely associated with MP activity.  \nIn this study, we aim to investigate the role of HA-GCX impairment in regulating MP and explore the underlying mechanisms. First, we demonstrated a positive correlation between HA-GCX thickness and MP activity in cancer cells. Then, we found that HA-GCX disruption could significantly inhibit MP by impairing actin-dependent membrane ruffle formation, thereby reducing cancer cell prolife","cbCaijJRKfADTdFR","https://ap.wps.com/l/cbCaijJRKfADTdFR","pdf",12486859,14,"English","# Abstract\n## Introduction\n## Materials and Methods","[{\"question\":\"How does HA-related glycocalyx (HA-GCX) influence macropinocytosis in cancer cells?\",\"answer\":\"HA-GCX thickness is positively correlated with macropinocytosis activity. Disrupting HA-GCX suppresses MP by decreasing membrane ruffle formation.\"},{\"question\":\"What molecular changes occur after HA-GCX removal?\",\"answer\":\"HA-GCX removal upregulates CDKN1A/p21 and its downstream targets MMP1/9. Knockdown of p21 or MMP1/9 can rescue macropinocytosis.\"},{\"question\":\"What is the evidence that HA-GCX breakdown can affect tumor growth in vivo?\",\"answer\":\"The study reports that HA-GCX digestion delays tumor growth in vivo by inhibiting the p21-MMP1/MMP9 axis-mediated MP.\"}]","Impairment of Hyaluronan-Related Glycocalyx Inhibits Macropinocytosis in Cancer Cells via p21 Upregulation | PDF",1790200478,35]