Liquiritigenin Alleviates Inflammation and Mitochondrial Dysfunction in Acute Pancreatitis via ERβ-VDAC1 Signaling.

Ethnopharmacological Relevance: Liquorice (Gancao), a classic Chinese herb, has been historically prescribed for inflammation and gastrointestinal disorders. Its bioactive flavonoid liquiritigenin (4',7-dihydroxyflavone) exhibits anti-inflammatory properties, yet its efficacy against acute pancreatitis (AP) remains unexplored.

Aim: To systematically investigate the therapeutic potential of liquiritigenin against AP and decipher its estrogen receptor beta (ERβ)-mediated mitochondrial regulatory mechanisms.

Methods: Employing caerulein-induced murine AP and sodium taurocholate-treated pancreatic acinar cell models, we quantified pancreatic injury and cellular damage. Temporal profiling of ERβ/estrogen receptor alpha (ERα) was correlated with disease progression, complemented by analysis of publicly available transcriptomic datasets. Multimodal approaches including network pharmacology, molecular docking, and transcriptomics identified ERβ-voltage-dependent anion channel 1 (VDAC1) as the pivotal axis, validated by: (i) ethylene glycol bis(succinimidyl succinate) crosslinking/Western blot for VDAC1 oligomerization, (ii) comparative studies with VDAC1 inhibitor VBIT-12, and (iii) mitochondrial assessments.

Results: Liquiritigenin significantly attenuated AP severity, reducing pancreatic enzymes and histopathological damage while suppressing inflammation. ERβ expression showed a stronger inverse correlation with disease severity than ERα. Mechanistically, liquiritigenin selectively upregulated ERβ protein without altering mRNA levels, and subsequent transcriptomic analysis identified VDAC1 as the key mitochondrial effector. Liquiritigenin inhibited VDAC1 oligomerization and preserved mitochondrial function, with efficacy comparable to the VDAC1 inhibitor VBIT-12. These findings establish the ERβ-VDAC1 axis as central to liquiritigenin's therapeutic action.

Conclusion: This study provides the first evidence that liquiritigenin, a selective ERβ agonist, protects against AP by inhibiting VDAC1 oligomerization and preserving mitochondrial homeostasis, thereby reducing inflammatory injury and pancreatic tissue damage. These findings highlight ERβ-VDAC1 signaling as a potential therapeutic target for AP.