| RRC ID |
86440
|
| Author |
Loo TM, Zhou X, Tanaka Y, Sugawara S, Yamauchi S, Kawasaki H, Matsuoka Y, Sugiura Y, Sakuma S, Yamanishi Y, Yotsumoto S, Dodo K, Shirasaki Y, Kamatani T, Takahashi A.
|
| Title |
Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis.
|
| Journal |
Nat Commun
|
| Abstract |
Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis. Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.
|
| Volume |
16(1)
|
| Pages |
6617
|
| Published |
2025-7-29
|
| DOI |
10.1038/s41467-025-61894-9
|
| PII |
10.1038/s41467-025-61894-9
|
| PMID |
40731111
|
| PMC |
PMC12307602
|
| MeSH |
Animals
Cell Line, Tumor
Cellular Senescence* / physiology
Cystine* / deficiency
Cystine* / metabolism
Ferroptosis* / drug effects
Ferroptosis* / physiology
Humans
Iron / metabolism
Lipid Peroxidation* / drug effects
Lysosomes* / drug effects
Lysosomes* / metabolism
Mice
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
|
| IF |
12.121
|
| Resource |
| Mice |
RBRC10170 |
