Background/Objectives: Poly (ADP-ribose) polymerase (PARP) inhibitors have shown significant efficacy in treating BRCA-mutated cancers; however, a significant proportion of patients fail to respond. Emerging evidence highlights the role of PARP in lipid metabolism, suggest-ing its modulation as a novel strategy to regulate tumor progression. Methods: In this study, lipidomics and transcriptomics analyses were conducted to elucidate the mechanisms underlying PARP inhibitor-induced ferroptosis and immune modulation in triple-negative breast cancer (TNBC). Results: We demonstrated that the PARP inhibitor Niraparib significantly reprograms lipid metabolism in TNBC cells, marked by elevated phosphatidylethanolamine (PE) and cholesterol ester (ChE) levels. This metabolic shift was mechanistically linked to upregulation of the cholesterol transporter NPC1L1 via the PARP1-RELA-NPC1L1 signaling axis, which subsequently activated the AKT pathway. Combinatorial treatment with Niraparib and either Ezetimibe (an NPC1L1 inhibitor) or AZD5363 (an AKT inhibitor) synergistically enhanced TNBC cell death by promoting ferroptosis through glutathione depletion and lipid peroxidation. Furthermore, NPC1L1 inhibition amplified PARP inhibitor-induced immune responses, increasing CD8⁺ T cell infiltration and cytotoxicity in tumors. Conclusions: In conclusion, our findings establish NPC1L1 as a critical mediator of PARP inhibitor efficacy and propose dual targeting of lipid metabolism, providing a new therapeutic approach for the combination treatment of TNBC.

Background/Objectives: Acute myeloid leukemia (AML) is an aggressive malignancy marked by high relapse rates and molecular heterogeneity, necessitating the identification of novel therapeutic targets. T-complex protein 1 (TCP1), a chaperonin implicated in protein folding, remains underexplored in AML pathogenesis. This study investigates the functional role of TCP1 in AML progression and evaluates its therapeutic potential. Methods: Using successive generations of xenografted tumor models, we systematically assessed the correlation between TCP1 expression and AML tumorigenicity. Functional consequences of TCP1 silence were evaluated through in vitro proliferation assays and in vivo tumor growth monitoring. Two distinct inhibitory strategies were employed: miR-340-5p-mediated transcriptional silencing and FTY720-induced disruption of TCP1 chaperone activity. Mechanistic insights were derived from ubiquitin–proteasome pathway analysis, cell cycle profiling, and apoptosis assays. Results: High TCP1 expression correlated strongly with enhanced AML tumorigenicity. Knockdown of TCP1 significantly inhibited AML cell growth and induced degradation of AML1-ETO and PLK1 proteins through the ubiquitin–proteasome pathway. miR-340-5p effectively silenced TCP1 expression, exhibiting an inverse correlation with TCP1 levels. FTY720 disrupted TCP1′s chaperone function, leading to cell cycle arrest, apoptosis, and reduced xenograft tumor growth in murine models. Conclusion: Our findings establish TCP1 as a promising therapeutic target for AML. Both miR-340-5p and FTY720 demonstrate potent anti-leukemic effects by suppressing TCP1 activity, highlighting their potential as novel strategies to inhibit AML proliferation and improve therapeutic outcomes.

Background: PARP inhibitors exhibit significant lethality in tumors with BRCA1/2 mutations or homologous recombination defects; however, their clinical application is limited by the rarity of BRCA1/2 mutations, complex resistance mechanisms, and limited efficacy of monotherapy. Objective: This study aimed to investigate how Niraparib induces dysregulation of sphingolipid metabolism—particularly upregulation of the key enzyme SPHK1—in triple-negative breast cancer (TNBC) cells, and to elucidate a novel super-enhancer (SE)-mediated mechanism of Niraparib resistance. We also applied AI-based virtual screening to identify compounds targeting key nodes and develop strategies for sensitizing TNBC to Niraparib. Results: Niraparib induced sphingolipid metabolic imbalance and significantly upregulated SPHK1 in TNBC. Multi-omics analyses revealed that SPHK1 is regulated by a super-enhancer. Mechanistically, Niraparib inhibited PARylation of the transcription factor SP1, enhancing its occupancy at the SE region and reactivating its transcriptional activity, thereby promoting SPHK1 expression. This process activated pro-survival signaling pathways and conferred niraparib resistance. AI-facilitated virtual screening identified the natural compound Echinatin as a potent SP1 inhibitor, which stably binds to SP1 and exhibits marked synergistic effects with Niraparib. While targeting downstream SPHK1 also provided therapeutic benefit by enhancing the anti-tumor efficacy of Niraparib, Echinatin demonstrates a superior advantage due to its more favorable toxicity profile. Conclusions: Niraparib induces resistance through the SP1-SE-SPHK1 axis, whereas Echinatin effectively reverses this mechanism by inhibiting the upstream regulator SP1, significantly potentiating the efficacy of Niraparib. This study reveals a novel molecular mechanism underlying Niraparib resistance and proposes a promising combination therapy strategy.