Agrimol B通过靶向S100A6-HDAC2-突变型p53乙酰化通路，在TP53突变型胰腺癌中诱导自噬性死亡。

Abstract

Elevated S100A6 is identified as a key regulator of mutant p53 stability in PDAC. • AgrB induces S100A6-dependent autophagic death in TP53-mutant PDAC cells. • AgrB enhances S100A6-HDAC2 interaction to reduce p53 K382 acetylation. Background Pancreatic ductal adenocarcinoma (PDAC) harbors TP53 mutations at high frequency, yet therapeutic strategies that specifically target mutant p53 remain limited. Purpose This study aimed to identify S100A6, a calcium-binding protein frequently upregulated in TP53-mutant PDAC, as a critical regulator of mutant p53 stability and tumor progression, and to explore potential S100A6-targeting agents for therapeutic intervention. Methods We integrated computer-assisted drug screening with transcriptomics, acetylation omics, and molecular biology techniques to identify Agrimol B (AgrB), a bioactive compound derived from the traditional Chinese herb Agrimonia pilosa Ledeb. , as a potential S100A6-targeting agent. Results High S100A6 expression was closely associated with poor prognosis in patients with TP53-mutant PDAC, whereas S100A6 depletion markedly suppressed PDAC cell growth and metastatic potential. Mechanistically, AgrB enhanced the interaction between S100A6 and the deacetylase HDAC2, leading to reduced acetylation of mutant p53 at lysine 382. This disruption activated autophagy-dependent cell death and thereby inhibited PDAC progression. Conclusion Our findings reveal an S100A6-HDAC2-mutant p53 acetylation axis that regulates TP53-mutant pancreatic tumorigenesis, providing mechanistic evidence supporting S100A6 as a therapeutic vulnerability and highlighting AgrB as a promising natural-product-derived candidate for further development against this aggressive malignancy. In TP53-mutant PDAC, S100A6 is highly expressed and supports malignant tumor growth. Under basal conditions, the interaction between S100A6 and HDAC2 is weak, leading to sustained acetylation of mutant p53 at lysine 382 and enhanced tumor cell proliferation. A