The process of intracellular proteolysis through ATP-dependent proteases is a biologically conserved phenomenon. The stress responses and bacterial virulence of various pathogenic bacteria are associated with the ATP-dependent Clp protease. In this study, a Brucella abortus 2308 strain, ΔclpP, was constructed to characterize the function of ClpP peptidase. The growth of the ΔclpP mutant strain was significantly impaired in the TSB medium. The results showed that the ΔclpP mutant was sensitive to acidic pH stress, oxidative stress, high temperature, detergents, high osmotic environment, and iron deficient environment. Additionally, the deletion of clpP significantly affected Brucella virulence in macrophage and mouse infection models. Integrated transcriptomic and proteomic analyses of the ΔclpP strain showed that 1965 genes were significantly affected at the mRNA and/or protein levels. The RNA-seq analysis indicated that the ΔclpP strain exhibited distinct gene expression patterns related to energy production and conversion, cell wall/membrane/envelope biogenesis, carbohydrate transport, and metabolism. The iTRAQ analysis revealed that the differentially expressed proteins primarily participated in amino acid transport and metabolism, energy production and conversion, and secondary metabolites biosynthesis, transport and catabolism. This study provided insights into the preliminary molecular mechanism between Clp protease to bacterial growth, stress response, and bacterial virulence in Brucella strains.

Schistosomiasis is a chronic helminthic disease of both humans and animals and the second most prevalent parasitic disease after malaria. Through a complex migration process, schistosome eggs trapped in the liver can lead to the formation of granulomas and subsequent schistosome-induced liver damage, which results in high mortality and morbidity. Although praziquantel can eliminate mature worms and prevent egg deposition, effective drugs to reverse schistosome-induced liver damage are scarce. High mobility group box 1 (HMGB1) is a multifunctional cytokine contributing to liver injury, inflammation, and immune responses in schistosomiasis by binding to cell-surface Toll-like receptors and receptors for advanced glycation end products. HMGB1 is increased in the serum of patients with schistosomiasis and enables hepatic stellate cells to adopt a proliferative myofibroblast-like phenotype, which is crucial to schistosome-induced granuloma formation. Inhibition of HMGB1 was found to generate protective responses against fibrotic diseases in animal models. Clinically, HMGB1 presents a potential target for treatment of the chronic sequelae of schistosomiasis. Here, the pivotal role of HMGB1 in granuloma formation and schistosome-induced liver damage, as well the potential of HMGB1 as a therapeutic target, are discussed.

Liquid–liquid phase separation (LLPS) has emerged as a fundamental regulatory mechanism in bacterial physiology, orchestrating essential cellular processes including gene expression, stress responses, metabolic homeostasis, and biofilm formation. This phenomenon is driven by intrinsically disordered regions (IDRs), multivalent interactions between modular domains, and dynamic protein‐nucleic acid associations, with precise modulation by environmental parameters such as temperature, ionic strength, and post‐translational modifications (PTMs). The resulting functional condensates confer enhanced environmental adaptability and contribute to antibiotic resistance mechanisms in bacterial populations. These assemblies further impact host‐pathogen interactions through modulation of virulence factor expression and immune evasion strategies, thereby complicating infection management. This comprehensive review systematically examines the molecular mechanisms driving LLPS, its dynamic regulatory networks, and physiological functions in bacteria. We evaluate the therapeutic potential of targeting LLPS pathways for antimicrobial development, with particular emphasis on antibiotic resistance regulation and intestinal commensal colonization. Future research should elucidate the mechanistic roles of LLPS‐associated biomacromolecules in bacterial physiology, characterize their assembly and disassembly dynamics, and explore their therapeutic applications to establish a theoretical foundation for innovative antimicrobial strategies.

The unfolded protein response (UPR) is a cellular stress response mechanism that maintains endoplasmic reticulum (ER) homeostasis through three signaling pathways mediated by IRE1α, PERK, and ATF6 sensors. While UPR's role in viral infections has been well documented, recent studies indicate that intracellular bacterial pathogens have evolved specific mechanisms to hijack UPR signaling for survival and replication. This review examines UPR manipulation strategies employed by major bacterial pathogens, including Brucella , Mycobacterium tuberculosis , Legionella , and Salmonella . These pathogens utilize effector proteins that target specific UPR components: Brucella effectors VceC, BspB, TcpB, and BspL interact with ER chaperones and ERAD machinery; M. tuberculosis proteins Rv0297, ESAT‐6, HBHA, and CdhM disrupt calcium homeostasis and alter ER morphology; Legionella Lpg0519 activates atypical ATF6 signaling; and bacterial toxins including cholera toxin bind IRE1α structural motifs for pathway activation. The molecular basis of UPR manipulation includes direct protein–protein interactions, calcium signaling interference, ER morphological disruption, and transcriptional program modulation. Bacterial hijacking of UPR pathways affects ER‐phagy processes and host immune responses, facilitating intracellular survival. UPR pathway components serve as potential targets for host‐directed therapy against persistent and drug‐resistant infections. Small molecule modulators targeting IRE1α kinase activity, PERK inhibitors, and ATF6 pathway regulators may complement conventional antimicrobial approaches. Characterization of these host‐pathogen interactions provides insights for developing therapeutic strategies that target bacterial dependencies on cellular stress responses.