Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation

Theranostics. 2022 Jan 1;12(2):976-998. doi: 10.7150/thno.63751. eCollection 2022.


Rationale: We found that a subset of signal transducer and activator of transcription 3 (STAT3) translocated into mitochondria in phagocytes, including macrophages isolated from individuals with sepsis. However, the role of mitochondrial STAT3 in macrophages remains unclear. Method: To investigate the function of mitochondrial STAT3 in vivo, we generated inducible mitochondrial STAT3 knock-in mice. A cytokine array analysis, a CBA analysis, flow cytometry, immunofluorescence staining and quantification and metabolic analyses in vivo were subsequently performed in an LPS-induced sepsis model. Single-cell RNA sequencing, a microarray analysis, metabolic assays, mass spectrometry and ChIP assays were utilized to gain insight into the mechanisms of mitochondrial STAT3 in metabolic reprogramming in LPS-induced sepsis. Results: We found that mitochondrial STAT3 induced NF-κB nuclear localization and exacerbated LPS-induced sepsis in parallel with a metabolic switch from mainly using glucose to an increased reliance on fatty acid oxidation (FAO). Moreover, mitochondrial STAT3 abrogated carnitine palmitoyl transferase 1a (CPT1a) ubiquitination and degradation in LPS-treated macrophages. Meanwhile, an interaction between CPT1a and ubiquitin-specific peptidase 50 (USP50) was observed. In contrast, knocking down USP50 decreased CPT1a expression and FAO mediated by mitochondrial STAT3. The ChIP assays revealed that NF-κB bound the USP50 promoter. Curcumin alleviated LPS-mediated sepsis by suppressing the activities of mitochondrial STAT3 and NF-κB. Conclusion: Our findings reveal that mitochondrial STAT3 could trigger FAO by inducing CPT1a stabilization mediated by USP50 in macrophages, at least partially.

Keywords: CPT1a stabilization; FAO; USP50; mitochondrial STAT3.

MeSH terms

  • Animals
  • Carnitine O-Palmitoyltransferase / metabolism*
  • Curcumin / pharmacology
  • Curcumin / therapeutic use
  • Fatty Acids / metabolism*
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Humans
  • Lipopolysaccharides / antagonists & inhibitors
  • Macrophage Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / metabolism*
  • Oxidation-Reduction
  • Phagocytes
  • STAT3 Transcription Factor / metabolism*
  • Sepsis / drug therapy
  • Sepsis / etiology
  • Sepsis / metabolism*


  • Fatty Acids
  • Lipopolysaccharides
  • Mitochondrial Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • CPT1B protein, mouse
  • Carnitine O-Palmitoyltransferase
  • Curcumin