SIRT3 (Sirtuin 3)

Our study identified SIRT expression in macrophages of the DLBCL environment and specifically the importance of SIRT1 in the DLBCL M1 macrophage immune microenvironment. This opens an avenue for the potential translational exploitation of SIRT1 modulation as therapeutic target in this hematological malignancy.

Distinct integrated sirtuin scores thus capture subtype-specific metabolic/epigenetic states and provide robust RFS stratification across BC subtypes. These findings highlight sirtuins as integrators of longevity pathways and tumor metabolism, suggesting therapeutically exploitable vulnerabilities along NAD⁺-dependent regulatory axes.

Key resistance pathways include: lactylated IGF2BP3 activating PCK2-NRF2 to counter lenvatinib-induced stress; ALDOA lactylation enhancing liver cancer stem cell self-renewal for chemoresistance; MOESIN lactylation in Regulatory T cells (Tregs) weakening anti-PD-1 efficacy. Therapeutically, 2-DG, AZD3965, or SIRT3 activators (reverse lactylation) restore drug sensitivity, alone or in combination. Despite limited specific detectors, lactylation is a promising target to overcome HCC drug resistance, aiding precision treatment.

These results indicate that the proteomic impact of SIRT3 modulation is strongly influenced by cellular metabolic context. All raw mass spectrometry data are publicly available in PXD063181.

Importantly, GS markedly inhibited OS tumor growth in vivo without causing detectable systemic toxicity. Collectively, our findings identify a mechanism distinct from the previously reported glycolysis/MAPK pathway, thereby broadening the mechanistic understanding of GS and underscoring its potential as a mitochondria-targeted therapeutic strategy for OS.

SIRT3 overexpression significantly reduced hepatic lipid accumulation, inflammation, oxidative stress, and fibrosis in HFD-and MCD diet-fed mice.

This effect is accompanied by coordinated modulation of PPARα/NF-κB, sirtuin, autophagy, and MMP pathways. These findings support further evaluation of carvacrol as a microenvironment-directed adjunct in breast cancer therapy.

Finally, we also documented an increase in mitochondria reactive oxygen species (mtROS). The combined inhibition of SIRT3 and activation of SIRT5 greatly reduces the size of spheroids through the inhibition of hypoxic response, which is then followed by the alteration of the autophagic and mitophagic process and the toxic accumulation of mitochondrial ROS, representing a new anti-tumoral strategy.

We further show silent mating type information regulation2 homolog-3 (SIRT3)-mediated deacetylation stabilizes TFAM, whereas SIRT3 downregulation promotes TFAM degradation via polyubiquitination. Together, our study reveals a novel mode of metabolic reprogramming due to the loss of TFAM and identifies the TFAM-G6PD axis as a metabolic vulnerability, offering a promising synthetic lethal therapeutic strategy for liver cancer.

Paeoniflorin exerts significant neuroprotective effects against SCI-induced injury by activating the SIRT3 signaling pathway and regulating apoptosis, oxidative stress, and ferroptosis, offering a novel potential therapeutic target for SCI treatment.