Figure 1 | Restoration of androgen receptor signaling. A | Androgen receptor reactivation. The mechanism of Enz in CRPC is shown in the left part of the cell. Various signalling pathways contribute to the activation of AR transcription and expression, involving FOXA1/CREB5/AR, IKBKE/Hippo/c-Myc/AR, and EphB4/c-Myc/AR pathways. Several inhibitors, which are associated with AR expression or targets of relevant pathways, are shown in red arrows. Especially, ARCC-4, UT-34, and IRF8 are AR degraders that directly act on AR.B | Androgen receptor splice variants and mutations. The truncated AR with a deleted LBD fails to bind with Enz. AR-V7 is the most common variant participating multiple signalling pathways, which are shown in black arrows. AR mutations contain F876L, F877L, H875Y, T878A/D891H, and T878A/S889G. Some of them can result in the alteration of Enz function that covert Enz into an agonist. Enz, enzalutamide; AR, androgen receptor; N, N-terminal domain; D, DNA-binding domain; L, carboxy-terminal ligand-binding domain; KLK3, kallikrein-related peptidase 3; TMPRSS2, transmembrane protease serine 2; BMI1, a polycomb group protein; PTC209, a BMI1 inhibitor; CREB5, cAMP-response element-binding protein 5; FOXA1, forkhead box protein A1; IKBKE, I-kappa-B kinase; Eph, erythropoietin-producing human hepatocellular; 4EBP1, eukaryotic initiation factor 4E-binding protein 1; eIF4F, eukaryotic translation initiation factor 4F, including eIF4A, eIF4E, and eIF4G; STAT3, signal transducer and activator of transcription 3; JAK, Janus kinase; GPA500, STAT3 inhibitor; Triptolide, AR/AR-Vs transactivation activity inhibitor; ARCC-4, proteolysis-targeting chimaeras (PROTACs) derivative; UT-34, the orally bioavailable AR degrader; IRF8-induced drugs, interferon regulatory factor 8; AR-V7, androgen receptor variant 7; AR-FL, full-length androgen receptor; hnRNPA1, splicing factor; ACK1, non-receptor tyrosine kinases; pY88-H4, Tyr88-phosphorylated histone H4; MLL2, a H3K4methyltransferase; WDR5, MLL2-interacting protein; AVPR1A, arginine vasopressin receptor 1a; VAV3, a Rho family guanosine triphosphatase guanine nucleotide exchange factor; SPT, supraphysiological testosterone; E2F, the transcription factor; DDR, DNA damage response; EZH2, zeste homologue 2; HSP, heat shock protein; STUB1, E3 ubiquitin ligase; AKR1C3, aldo-keto reductase family 1 member C3; BCL2, B cell lymphoma-2; ABT263, BCL2 protein inhibitor; USP26, ubiquitin specific protease 26; IPI-9119, fatty acid synthase inhibitor; Luteolin, AR-V7 inhibitor; GATA2, GATA binding protein 2; BET, bromodomain and extra-terminal; JQI/I-BET762, small-molecule BET inhibitor; BRD4, amino-terminal bromodomains of bromodomain-containing protein 4; ZFX, zinc-finger transcription factor; PARP, poly ADP-ribose polymerase; H12, helix 12; ASC-J9®, AR degradation enhancer; JJ-450, a AR antagonist.