CTRP3 alleviates neuropathic pain by improving mitochondrial biogenesis and mitochondrial unfolded protein response via spinal SIRT1 in rats

Int J Mol Med. 2026 Jul;58(1):197. doi: 10.3892/ijmm.2026.5868. Epub 2026 May 22.

ABSTRACT

Neuropathic pain arises from an intricate network of interconnected pathophysiological mechanisms, yet the arsenal of effective therapeutic strategies remains frustratingly limited. Accumulating evidence has linked mitochondrial dysfunction to the progression of neuropathic pain. C1q‑tumor necrosis factor‑related protein‑3 (CTRP3), a newly identified adipokine with diverse cytoprotective capacities, has not been previously explored for its role in nociceptive processing. To explore the role of CTRP3 in pain hypersensitivity, pain‑related behavioral assessments were conducted using von Frey filaments and acetone drop method in male rats subjected to spared nerve injury (SNI). To unravel the underlying mechanisms, spinal cord tissues were subjected to western blotting, reverse transcription‑quantitative PCR, immunofluorescence staining, dihydroethidium staining, small interfering RNA (siRNA) technologies and biochemical assays for quantifying oxidative markers. The findings showed that SNI markedly reduced endogenous CTRP3 expression in spinal neurons. Intrathecal administration of recombinant CTRP3 (rCTRP3) alleviated mechanical allodynia and cold hyperalgesia in SNI‑induced rats. Additionally, rCTRP3 treatment enhanced PGC‑1α‑mediated mitochondrial biogenesis, ATF5‑triggered mitochondrial unfolded protein response (UPR^mt), and mitigated spinal oxidative stress. Mechanistically, pharmacological inhibition of SIRT1 with EX‑527, or siRNA‑mediated silencing of PGC‑1α or ATF5, reversed the effects of CTRP3 on pain hypersensitivity, mitochondrial biogenesis, UPR^mt and oxidative stress. The present study demonstrates that CTRP3 mitigates mechanical allodynia and cold hyperalgesia in male SNI rats by activating spinal SIRT1, thereby enhancing PGC‑1α‑mediated mitochondrial biogenesis and ATF5‑induced UPR^mt. CTRP3 may therefore represent a novel therapeutic target for the management of neuropathic pain.

PMID:42169654 | DOI:10.3892/ijmm.2026.5868