In recent years, the role of mitochondria in pathogenic fungi in terms of azole resistance and fungal pathogenicity has been a rapidly developing field. In this review, we describe the molecular mechanisms by which mitochondria are involved in regulating azole resistance and fungal pathogenicity. Mitochondrial function is involved in the regulation of drug efflux pumps at the transcriptional and posttranslational levels. On the one hand, defects in mitochondrial function can serve as the signal leading to activation of calcium signaling and the pleiotropic drug resistance pathway and, therefore, can globally upregulate the expression of drug efflux pump genes, leading to azole drug resistance. On the other hand, mitochondria also contribute to azole resistance through modulation of drug efflux pump localization and activity. Mitochondria further contribute to azole resistance through participating in iron homeostasis and lipid biosynthesis. Additionally, mitochondrial dynamics play an important role in azole resistance. Meanwhile, mitochondrial morphology is important for fungal virulence, playing roles in growth in stressful conditions in a host. Furthermore, there is a close link between mitochondrial respiration and fungal virulence, and mitochondrial respiration plays an important role in morphogenetic transition, hypoxia adaptation, and cell wall biosynthesis. Finally, we discuss the possibility for targeting mitochondrial factors for the development of antifungal therapies.

Stringent regulation of the transcription factor NF-κB signaling is essential for the activation of host immune responses and maintaining homeostasis, yet the molecular mechanisms involved in its tight regulation are not completely understood. In this study, we report that IKK-interacting protein (IKIP) negatively regulates NF-κB activation. IKIP interacted with IKKα/β to block its association with NEMO, thereby inhibiting the phosphorylation of IKKα/β and the activation of NF-κB. Upon LPS, TNF-α, and IL-1β stimulation, IKIP-deficient macrophages exhibited more and prolonged IKKα/β phosphorylation, IκB, and p65 phosphorylation and production of NF-κB–responsive genes. Moreover, IKIP-deficient mice were more susceptible to LPS-induced septic shock and dextran sodium sulfate–induced colitis. Our study identifies a previously unrecognized role for IKIP in the negative regulation of NF-κB activation by inhibition of IKKα/β phosphorylation through the disruption of IKK complex formation.

CARD9 is an essential adaptor protein in antifungal innate immunity mediated by C-type lectin receptors. The activity of CARD9 is critically regulated by ubiquitination; however, the deubiquitinases involved in CARD9 regulation remain incompletely understood. In this study, we identified ovarian tumor deubiquitinase 1 (OTUD1) as an essential regulator of CARD9. OTUD1 directly interacted with CARD9 and cleaved polyubiquitin chains from CARD9, leading to the activation of the canonical NF-κB and MAPK pathway. OTUD1 deficiency impaired CARD9-mediated signaling and inhibited the proinflammatory cytokine production following fungal stimulation. Importantly, Otud1^–/– mice were more susceptible to fungal infection than wild-type mice in vivo. Collectively, our results identify OTUD1 as an essential regulatory component for the CARD9 signaling pathway and antifungal innate immunity through deubiquitinating CARD9. Key Points OTUD1 deubiquitinates CARD9. OTUD1 positively regulates CLR-induced signaling and cytokine production. OTUD1 protects mice against C. albicans–induced fungal infection.

The IκB kinase (IKK) complex plays a vital role in regulating the NF-κB activation. Aberrant NF-κB activation is involved in various inflammatory diseases. Thus, targeting IKK activation is an ideal therapeutic strategy to cure and prevent inflammatory diseases related to NF-κB activation. In a previous study, we demonstrated that IKK-interacting protein (IKIP) inhibits the phosphorylation of IKKα/β and the activation of NF-κB through disruption of the formation of IKK complex. In this study, we identified a 15-aa peptide derived from mouse IKIP (46–60 aa of IKIP), which specifically suppressed IKK activation and NF-κB targeted gene expression via disrupting the association of IKKβ and NEMO. Importantly, administration of the peptide reduced LPS-induced acute inflammation and attenuated Zymosan-induced acute arthritis in mice. These findings suggest that this IKIP peptide may be a promising therapeutic reagent in the prevention and treatment of inflammatory diseases.

This study investigates the pivotal role of the molecular chaperone Hsp90 in the growth, development, and immune modulation of the opportunistic pathogen Aspergillus fumigatus . Using a Tet-on system-based conditional expression strain, Tet-hsp90 , we demonstrate that Hsp90 is essential for the growth and viability of A. fumigatus . In strains with suppressed Hsp90 expression, we observe a significant reduction in antioxidant capacity, an increase in intracellular reactive oxygen species levels, and a marked decrease in the activity of key antioxidant enzymes, such as superoxide dismutase and catalase, highlighting Hsp90’s critical role in regulating oxidative stress tolerance. Furthermore, the absence of Hsp90 leads to disruptions in metal ion metabolism, including copper, iron, and manganese, which further compromises the fungal cell’s ability to manage oxidative stress. Immune response analysis revealed that after Hsp90 inhibition, spores significantly increased the expression of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor alpha, in host cells. Further research showed that, upon Hsp90 inhibition, spores enhanced the phosphorylation of NF-κB p65 and ERK proteins, thereby activating these key signaling pathways to upregulate immune responses. In conclusion, this study underscores the multifaceted regulatory roles of Hsp90 in oxidative stress resistance, metal ion homeostasis, and immune system activation, providing valuable insights for the development of novel antifungal therapeutic strategies targeting Hsp90. IMPORTANCE: The significance of this study lies in its focused and in-depth analysis of the critical roles of the molecular chaperone Hsp90 in oxidative stress tolerance, metal ion homeostasis, and immune response regulation in Aspergillus fumigatus . Utilizing the Tet-on system to precisely modulate Hsp90 expression, this research demonstrates that Hsp90 is essential for the growth, development, and pathogenicity of this major opportunistic pathogen. Specifically, the study highlights Hsp90's crucial role in sustaining antioxidant enzyme activity, maintaining metal ion balance, and regulating immune responses—key factors that enable the fungus to survive and infect the host. These findings provide novel insights into the molecular mechanisms that underlie A. fumigatus 's resistance to oxidative stress and its evasion of host immunity, positioning Hsp90 as a promising therapeutic target for treating fungal infections. Furthermore, the results open new avenues for future investigations into the role of Hsp90 in fungal pathogenesis and immune modulation, potentially guiding the development of targeted antifungal therapies.

Atherosclerosis (AS) is a chronic cardiovascular disease. Traditional lipid-lowering treatments have not fully reduced the risk of disease onset in high-risk patients. This review provides a systematic overview of immune microenvironment remodeling and the mechanisms of pyroptosis during the onset and progression of atherosclerosis. Studies have shown that AS is not only related to abnormal lipid metabolism, but also closely associated with inflammatory responses, activation of immune cells, and programmed cell death. Immune cells, including macrophages, T cells, and B cells, play key roles in plaque formation, progression, and rupture. At the same time, NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis exacerbates plaque instability by promoting the release of inflammatory mediators, including Interleukin-1β (IL-1β) and interleukin-18 (IL-18), We further summarize emerging therapeutic strategies targeting immune regulation and pyroptosis pathways, including NLRP3 inhibitors, cytokine-targeted agents, and nano-drug delivery systems, thereby offering new perspectives for the precise treatment of AS.