Tomczyk, M. M. | bioRxiv Science

bioRxiv2026

Autophagy Cholesterol Axis Remodeling Supports Malignant Progression and Chemoresistance in Glioma

Glioma progression and resistance to temozolomide (TMZ) remain major clinical challenges. Here, we investigated whether dysregulated autophagy and cholesterol metabolism are coordinately remodeled during glioma progression and TMZ resistance. Tissue microarray analysis of astrocytoma and glioblastoma specimens revealed progressive autophagosome accumulation, reflected by increased LC3{beta} puncta, coupled with impaired autophagic flux compared with adjacent normal brain tissue. These alterations intensified with tumor grade and were associated with upregulation of farnesyl diphosphate synthase (FDPS), linking malignant progression to cholesterol pathway remodeling. TMZ-resistant (R) glioblastoma cells exhibited epithelial-to-mesenchymal transition, mitotic quiescence, and mitochondrial remodeling consistent with a therapy-tolerant phenotype. Bioenergetic profiling demonstrated reduced respiratory reserve, diminished ATP-linked respiration, and elevated proton leak, indicating constrained metabolic flexibility. In parallel, impaired autophagy flux was associated with suppression of de novo cholesterol synthesis and transcriptional downregulation of SREBP-2 and LDL-R. Comprehensive lipidomic profiling revealed marked cholesterol metabolic reprogramming in R cells, characterized by accumulation of specific cholesteryl esters, including CE 22:5, CE 22:6, CE 22:4, and CE 20:4, despite reduced cholesterol biosynthesis. Pharmacologic inhibition of the mevalonate pathway with simvastatin significantly altered cholesteryl ester profiles but failed to restore autophagy flux or sensitize R cells to TMZ-induced apoptosis, even under combined TMZ-simvastatin treatment. Lay AbstractAs gliomas progress from astrocytoma to glioblastoma, autophagy becomes dysregulated and cholesterol metabolism is rewired. This coordinated remodeling supports tumor survival, metabolic plasticity, and resistance to temozolomide therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/697885v2_ufig1.gif" ALT="Figure 1000"> View larger version (79K): org.highwire.dtl.DTLVardef@1183dd2org.highwire.dtl.DTLVardef@82e20dorg.highwire.dtl.DTLVardef@c6c8dforg.highwire.dtl.DTLVardef@adb427_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsAutophagy flux blockade intensifies during progression from astrocytoma to glioblastoma Dysregulated autophagy is coupled to altered cholesterol metabolism in malignant gliomas TMZ-resistant glioblastoma cells undergo epithelial-to-mesenchymal transition and mitotic quiescence Resistant cells exhibit constrained bioenergetic capacity and mitochondrial remodeling Impaired autophagy suppresses de novo cholesterol synthesis and lipid recycling Lipidomics reveals accumulation of long-chain cholesteryl esters in TMZ-resistant cells Statin-based cholesterol inhibition fails to resensitize glioblastoma cells to temozolomide

cancer biology↗

bioRxiv2019

Non-nutritive sweetener consumption during pregnancy affects adiposity in mouse and human offspring

Overweight and obesity affect over 20% of children worldwide. Emerging evidence shows that nonnutritive sweeteners (NNS) could adversely influence weight gain and metabolic health, particularly during critical periods of development. Thus, we aimed to investigate the impact of prenatal NNS exposure on postnatal growth and adiposity. Among 2298 families participating in the CHILD cohort study, children born to mothers who regularly consumed NNS during pregnancy had elevated body mass index and adiposity at 3 years of age. In a complementary study designed to eliminate confounding by human lifestyle factors and investigate causal mechanisms, we exposed pregnant mice and cultured adipocytes to NNS (aspartame or sucralose) at doses relevant to human consumption. In mice, maternal NNS exposure caused elevated body weight, adiposity and insulin resistance in offspring, especially in males. Further, in 3T3-L1 pre-adipocyte cells, sucralose exposure during early stages of differentiation caused increased lipid accumulation and expression of adipocyte differentiation genes (e.g. C/EBP-, FABP4, FAS). The same genes were upregulated in the adipose tissue of male mouse offspring born to sucralose-fed dams. Together, these clinical and experimental findings provide evidence suggesting that maternal NNS consumption induces obesity risk in the offspring through effects on adiposity and adipocyte differentiation.\n\nOne Sentence SummaryMaternal consumption of non-nutritive sweeteners during pregnancy stimulates adipocyte differentiation, insulin resistance, weight gain, and adiposity in mouse and human offspring.

developmental biology↗