# 4-phenylbutyric acid improves sepsis-induced cardiac dysfunction by modulating amino acid metabolism and lipid metabolism via Comt/Ptgs2/Ppara

## TL;DR

This study shows that 4-phenylbutyric acid (PBA) helps reduce heart damage in sepsis by affecting amino acid and lipid metabolism through specific genes.

## Contribution

The study identifies Comt/Ptgs2/Ppara as key targets of PBA in protecting the heart during sepsis.

## Key findings

- PBA alleviated sepsis-induced cardiac damage in a mouse model.
- Metabolomics revealed 28 metabolites involved in PBA's therapeutic effects.
- Network pharmacology identified 7 key targets, including Comt, Ptgs2, and Ppara.

## Abstract

Cardiac dysfunction after sepsis the most common and severe sepsis-related organ failure. The severity of cardiac damage in sepsis patients was positively associated to mortality. It is important to look for drugs targeting sepsis-induced cardiac damage. Our previous studies found that 4-phenylbutyric acid (PBA) was beneficial to septic shock by improving cardiovascular function and survival, while the specific mechanism is unclear.

We aimed to explore the specific mechanism and PBA for protecting cardiac function in sepsis.

The cecal ligation and puncture-induced septic shock models were used to observe the therapeutic effects of PBA on myocardial contractility and the serum levels of cardiac troponin-T. The mechanisms of PBA against sepsis were explored by metabolomics and network pharmacology.

The results showed that PBA alleviated the sepsis-induced cardiac damage. The metabolomics results showed that there were 28 metabolites involving in the therapeutic effects of PBA against sepsis. According to network pharmacology, 11 hub genes were found that were involved in lipid metabolism and amino acid transport following PBA treatment. The further integrated analysis focused on 7 key targets, including Comt, Slc6a4, Maoa, Ppara, Pparg, Ptgs2 and Trpv1, as well as their core metabolites and pathways. In an in vitro assay, PBA effectively inhibited sepsis-induced reductions in Comt, Ptgs2 and Ppara after sepsis.

PBA protects sepsis-induced cardiac injury by targeting Comt/Ptgs2/Ppara, which regulates amino acid metabolism and lipid metabolism. The study reveals the complicated mechanisms of PBA against sepsis.

The online version contains supplementary material available at 10.1007/s11306-024-02112-3.