Protein post-translational modifications (PTMs) play pivotal roles in diverse physiological processes, including DNA damage response (DDR), cellular metabolism, and immune regulation. Our research has identified several deubiquitinases—such as OTUB1, OTUB2, OTUD6A, USP38, and A20—that critically regulate these pathways by modulating key effector proteins. Our functional studies demonstrate that depletion of these deubiquitinating enzymes (DUBs) significantly impacts tumor proliferation and drug resistance, underscoring their importance in oncogenic signaling and therapeutic response. Recently, we uncovered a novel nuclear function of ALDOA in inflammation-driven pancreatic carcinogenesis, where it amplifies tumor progression by activating NF-κB signaling in a ubiquitination-dependent manner. Specifically, TNFα stimulation induces K11- and K29-linked ubiquitination of ALDOA at Lys200, which enhances its interaction with RelA/p65 and facilitates nuclear translocation via importin-β. This process establishes a positive feedback loop in the tumor microenvironment by upregulating TNF-α expression in pancreatic ductal adenocarcinoma (PDAC). We further identified USP4 as a key negative regulator that counteracts ALDOA ubiquitination. Unlike broad ALDOA inhibition—which disrupts glycolysis—targeted suppression of ALDOA ubiquitination selectively blocks inflammation-induced proliferation, thereby enhancing chemosensitivity and synergizing with p65-directed anti-inflammatory therapy in combination chemotherapy. Collectively, our findings elucidate the multifaceted oncogenic mechanisms of ALDOA, spanning metabolic reprogramming and transcriptional regulation, while proposing novel therapeutic strategies to disrupt inflammation-fueled PDAC progression.