Sodium butyrate upregulates URAT1-mediated urate reabsorption in HK2 cells by activating FFAR2/p38 MAPK/ELK1/ARRB2 axis and relieving NF-κB–HNF1β competitive binding

Cheng Cao

doi:10.1016/j.bcp.2026.118308

Sodium butyrate upregulates URAT1-mediated urate reabsorption in HK2 cells by activating FFAR2/p38 MAPK/ELK1/ARRB2 axis and relieving NF-κB–HNF1β competitive binding

2026-08-03

0

PRE

AI

C

Cheng Cao

M

Mubin Sun

J

Jiabao Li

Z

Zhenyu Yuan

Y

Yuwei Gu

Y

Yufan Shao

L

Lisheng Wang

X

Xiaohua Jin

Y

Yijie Cheng *

B

Bo Fan *

DOI：10.1016/j.bcp.2026.118308

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Urate transporter 1 (URAT1, encoded by SLC22A12) is a key mediator of renal urate reabsorption and an important pharmacological target for urate-related disorders. Sodium butyrate (BuNa), a gut microbiota derived short-chain fatty acid, has been implicated in host metabolic regulation, but its role in renal urate transport remains unclear. Here, using molecular docking, cellular thermal shift assays, immunoprecipitation-mass spectrometry and multi-omics analyses, we identified free fatty acid receptor 2 (FFAR2) as a direct target of BuNa in renal proximal tubular HK2 cells . BuNa binding upregulated FFAR2 and promoted URAT1 expression and urate uptake via an FFAR2-dependent pathway. Mechanistically, BuNa/FFAR2 signaling acts via GNAQ to activate PLCβ, generating diacylglycerol and engaging a PKC-dependent p38 MAPK/ELK1 cascade that upregulates arrestin beta 2 (ARRB2). ARRB2 directly binds to IκB, preventing its phosphorylation-dependent degradation, thereby stabilizing IκB and inhibiting NF-κB nuclear translocation. Within the SLC22A12 promoter, NF-κB (RELA/p50) and hepatocyte nuclear factor 1 beta (HNF1β) compete for overlapping binding sites. By blocking NF-κB nuclear entry, BuNa relieves this competition, permitting HNF1β-driven SLC22A12 transcription. Thus, BuNa enhances URAT1-mediated urate reabsorption in HK2 cells via an FFAR2/GNAQ/p38 MAPK/ELK1/ARRB2 axis that stabilizes IκB, suppresses NF-κB, and relieves the competitive binding between NF-κB and HNF1β on the SLC22A12 promoter. These findings establish a previously unrecognized gut microbiota–kidney axis linking microbial BuNa to renal urate homeostasis through a novel transcriptional regulatory circuit.

Sodium butyrate upregulates URAT1-mediated urate reabsorption in HK2 cells by activating FFAR2/p38 MAPK/ELK1/ARRB2 axis and relieving NF-κB–HNF1β competitive binding

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