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Cell Death & Disease

Cell Death & Disease

IF: 8.1
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Activating PIK3CA mutation promotes overgrowth of adipose tissue via inhibiting lipophagy in macrodactyly

Published:6 October 2025 DOI: 10.1038/s41419-025-08024-x PMID: 41052995
Yating Yin,?Xiao Zhang,?Shihui Lin,?Zhibo Wang,?Baoxing Tian,?Xinyi Dai,?Aiping Yu,?Huixiao Li,?Hailei Mao,?Bin Wang

Abstract

Excessive proliferation and lipid accumulation of adipose tissue are the main pathological alterations in macrodactyly. Our previous studies found that macrodactyly exhibits abnormal lipid metabolism and inhibited autophagy, but the underlying mechanisms remain unclear. This study aims to investigate the regulatory mechanisms of autophagy in macrodactyly. The therapeutic impact and underlying mechanisms of autophagy on lipid accumulation, induced by a gain-of-function mutation of PIK3CA in macrodactyly, were assessed with respect to autophagy, lipid metabolism, oxidative stress, and deubiquitination. Autophagy deficiency resulting from PIK3CA mutation in macrodactyly led to excessive accumulation of adipose tissue. Lipid accumulation can be mitigated by inducing lipophagy of lipid droplets (LDs) in adipose derived stem cells of macrodactyly (Mac-ADSCs). The subsequent increase in free fatty acids (FFA) led to mitochondrial oxidative stress in Mac-ADSCs. Inducing autophagy exacerbated mitochondrial oxidative stress in Mac-ADSCs, thereby contributing to apoptosis. Additionally, the ablation of the deubiquitinase USP15 facilitated the degradation of LDs in Mac-ADSCs, through ubiquitin-dependent macrolipophagy. USP15 inhibitor reduced lipid accumulation in macrodactyly adipose tissue xenografts. In conclusion, activating PIK3CA mutation promotes excessive proliferation and lipid accumulation of Mac-ADSCs by inhibiting lipophagy. Targeted inhibition of USP15 may serve as a promising therapeutic approach for treating macrodactyly. A schematic illustrates that activating PIK3CA mutation promotes overgrowth of adipose tissue via inhibiting lipophagy in macrodactyly.

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Dimethyl sulfoxide 67-68-5 C2H6OS 1925 suppliers $5.00-$120900.00
Dimethyl sulfoxide 67-68-5 C2H6OS 1925 suppliers $5.00-$120900.00
Dimethyl sulfoxide 67-68-5 C2H6OS 1925 suppliers $5.00-$120900.00
Dimethyl sulfoxide 67-68-5 C2H6OS 1925 suppliers $5.00-$120900.00
Polyethylene Glycol 25322-68-3 (C2H4O)nH2O 1575 suppliers $5.00-$3550.00
Polyethylene Glycol 25322-68-3 (C2H4O)nH2O 1575 suppliers $5.00-$3550.00
Polyethylene Glycol 25322-68-3 (C2H4O)nH2O 1575 suppliers $5.00-$3550.00
Polyethylene Glycol 25322-68-3 (C2H4O)nH2O 1575 suppliers $5.00-$3550.00
Tween 80 9005-65-6 C24H44O6 1057 suppliers $15.00-$2720.00
Tween 80 9005-65-6 C24H44O6 1057 suppliers $15.00-$2720.00

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